Benzo(F)quinolinones

ABSTRACT

This invention relates to hexa- and octahydrobenzo[f]quinolin-3-ones, pharmaceutical formulations containing those compounds and methods of their use as steroid 5α-reductase inhibitors.

This application is a division of application Ser. No. 08/223,884, filedApr. 6, 1994, now U.S. Pat. No. 5,495,021 which is a divisional ofapplication Ser. No. 08/052,960, filed Apr. 23, 1993, now U.S. Pat. No.5,334,767, which is a divisional of application Ser. No. 07/927,710,filed Aug. 10, 1992, now U.S. Pat. No. 5,239,075, which is acontinuation-in-part of application Ser. No. 07/781,039, filed Oct. 21,1991, now abandoned, which is a continuation-in-part of application Ser.No. 07/748,116, filed Aug. 21, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to hexa- andoctahydrobenzo[f]quinolinones, pharmaceutical formulations containingthose compounds and their use as steroid 5α-reductase inhibitors.

It is generally known that certain undesirable physiological conditionssuch as benign prostatic hyperplasia, male pattern baldness, achevulgaris, seborrhea, androgenic alopecia, hirsutism and prostatic cancerare androgen mediated conditions dependent on 5α-dihydrotestosterone(DHT).

The enzyme 5α-reductase mediates the conversion of testosterone to themore potent androgen DHT locally, in the target organ. It has beenpostulated, and demonstrated, that inhibitors of 5α-reductase shouldblock the formation of DHT and bring about amelioration of the aboveundesirable physiological conditions. Recently, two 5α-reductaseisozymes (designated types 1 and 2) have been described in humans,Andersson et al., Proc. Natl. Acad. Sci. U.S.A., 87, 3640-3644,(1990;Andersson et al., Nature, 354, 159-161 (1991). In addition to certainstructural differences, the two isozymes exhibit some differences withrespect to their biochemical properties, expression patterns, genetics,and pharmacology, Andersson et al., Nature, 354, 159-161 (1991);Jenkins, et al., Journal of Clinical Investigation, 89, 293-300 (1992).Further elucidation of the roles that the two 5α-reductase isozymes playin androgen action is currently the subject of intense research. Theseisozymes are generally described as 5α-reductase 1 or 2, or type 1 ortype 2 5α-reductase.

Compounds reportedly useful for inhibiting 5α-reductase are generallysteroid derivatives such as the azasteroids in Rasmusson, et al., J.Med. Chem., 29, (11), 2298-2315 (1986); and benzoylaminophenoxy-butanoicacid derivatives such as those disclosed in EPO 291 245.

Certain benzo[f]quinolinone compounds are known. See, for example,Cannon, et al., Synthesis, 6, 494-496 (1988); Kiguchi, et al.,Heterocycles, 18, (Special Issue), 217-220 (1982); Cannon et al., J.Med. Chem., 22, (4), 341-347 (1979); Cannon, et al., J. Med. Chem., 23(1), 1-5 (1980); Ninomiya, et al., J. Med. Chem. Soc. Perkin Trans. 1,12, 2911-2917 (1984; and Horri, et al., Chem, Pharm. Bull., 16, (4),668-671 (1968). These references generally are directed toward thesynthesis and dopaminergic evaluation of the compounds disclosedtherein. The references do not suggest the novel hexa- andoctahydrobenzo[f]quinolinones of the present invention, as definedbelow, or that such compounds would be expected to have utility assteroid 5α-reductase inhibitors.

Accordingly, it is one object of the present invention to provide novelhexa- and octahydrobenzo[f]quinolinones which are potent selectivesteroid-5α-reductase inhibitors useful in the treatment of benignprostatic hyperplasia, male pattern baldness, acne vulgaris, seborrhea,androgenic alopecia, hirsutism and prostatic cancer.

A further object of the present invention is to provide therapeuticcompositions for treating said conditions.

Still another object is to provide methods for treating said conditions.

Other objects, features and advantages will become apparent to thoseskilled in the art from the following description and claims.

SUMMARY OF THE INVENTION

The present invention provides novel hexa- andoctahydrobenzo[f]quinolin-3-ones which are effective steroid5α-reductase inhibitors.

More specifically, this invention relates to compounds having theFormula ##STR1## where

R is hydrogen, C₁ -C₄ alkyl, unsubstituted or substituted phen(C₁-C₄)alkyl;

Z and Z¹ are independently selected from hydrogen and C₁ -C₄ alkyl orone of Z and Z¹ combines with R⁵ to form a carbon-carbon bond;

Y is hydrogen or methyl or combines with R¹ to form a carbon-carbonbond;

R¹ is hydrogen or combines with one of Y or R³ to form a carbon-carbonbond;

R² is hydrogen or C₁ -C₄ alkyl;

R³ is hydrogen or combines with R¹ to form a carbon-carbon bond;

R⁴ is hydrogen or combines with R⁵ to form a carbon-carbon-bond;

R⁵ is hydrogen or combines with one of Z or Z¹ to form a carbon-carbonbond;

n is 1 or 2;

X is hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto,C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group--A--R⁶ where A is C₁ -C₆ alkylene C₂ -C₆ alkenylene or C₂ -C₆alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁ -C₆ alkoxy, carboxy, C₁-C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino,amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl, or apharmaceutically acceptable salt thereof; provided that

(a) at least one of R¹ and R⁵ is hydrogen;

(b) when R is hydrogen, methyl, ethyl or benzyl, X is other thanhydrogen or methoxy; and

(c) when R is methyl, R² is other than methyl.

This invention also provides pharmaceutical formulations which comprise,a compound of the above Formula I, or a pharmaceutically acceptable saltthereof in association with a pharmaceutically acceptable carrier,diluent, or excipient.

A further embodiment of the present invention is a method for inhibiting5α-reductase. More particularly, further embodiments are methods fortreating a variety of disorders which have been linked to 5α-reductaseactivity in mammals. Included among those disorders are benign prostatichyperplasia, male pattern baldness, acne vulgaris, seborrhea, androgenicalopecia, hirsutism and prostatic cancer. These methods employ acompound of Formula I or a pharmaceutically acceptable salt thereof.Although the compounds of the present invention inhibit both5α-reductase isozymes, said compounds exhibit greater selectivity astype 1 5α-reductase inhibitors.

A further embodiment of this invention is a class of novel intermediatesuseful in the preparation of compounds of this invention as well as aprocess for preparing substantially pure optically active compounds ofthe present invention.

The intermediates have the Formula ##STR2## where

X is hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto,C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group--A--R⁶ where A is C₁ -C₆ alkylene, C₂ -C₆ alkenylene or C₂ -C₆alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁ -C₆ alkoxy, carboxy, C₁-C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino,amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl; and n is1 or 2; or a pharmaceutically acceptable salt thereof.

The process aspect of this invention which employs the intermediate ofFormula II is a process for preparing a substantially pure opticallyactive compound having the Formula ##STR3## where

R is hydrogen, C₁ -C₄ alkyl, unsubstituted or substituted phen(C₁-C₄)alkyl;

z and Z¹ are independently selected from hydrogen and C₁ -C₄ alkyl;

Y is methyl;

R² is hydrogen or C₁ -C₄ alkyl;

n is 1 or 2;

X is hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,carboxy, C₁ -C₆ alkoxy-carbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto,C₁ -C₆ alkthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group--A--R⁶ where A is C₁ -C₆ alkylene or C₂ -C₆ alkenylene or C₂ -C₆alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁ -C₆ alkoxy, carboxy, C₁-C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino,amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl, or apharmaceutically acceptable salt thereof; which comprises

a) reacting a 1-methyl-2-tetralone with an optically active amine toafford a corresponding 1-methylenamine; and

b) reacting the 1-methylenamine with an α, β-unsaturated carbonylcompound to afford a corresponding methanobenzocyclooctane -4-one; and

c) reacting the methanobenzocyclooctane -4-one with an acidic or basiscatalyst to afford a corresponding2,3,4,4a,9,10-hexahydro-4a-methyl-phenanthren-2-one; and

d) oxidatively cleaving said phenanthren-2-one to afford a corresponding3-[1-methyl-1-(2-keto-1,2,3,4-tetrahydronaphthyl)]propionic acid; and

e) reacting said propionic acid with ammonia or a primary amine toafford a corresponding10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one; and

f) reducing said hexahydrobenzo[f]quinolin-3-one to afford anoctahydrobenzo[f]-quinolin-3-one as defined above.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" means a straight or branched alkylradical having the stated number of carbon atoms. Such alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl and, where indicated, higher homologs and isomerssuch as n-pentyl, n-hexyl, 2-methylpentyl and the like.

The term "alkylene" means a bivalent straight chain alkyl radical havingthe stated number of carbon atoms such as methylene, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl.Similarly, "alkenylene" means a bivalent unsaturated straight chainhydrocarbon group having the stated number of carbon atoms and a singlecarbon-carbon double bond such as vinylene, 1-propene-1,3-diyl,2-propene-1,3-diyl, 2-butene-1,4-diyl, 1-butene-1,4-diyl and the like.Also similarly, "alkynylene" means a bivalent straight chain hydrocarbongroup having the stated number of carbon atoms and a singlecarbon-carbon triple bond such as 1,2-acetylenediyl, 1-propyne-1,3-diyl,2-butyne-1,4-diyl the like.

The term "phen(C₁ -C₄)alkyl" means a one to four carbon, straight orbranched chain, alkyl radical monosubstituted with an unsubstituted orsubstituted phenyl ring where the substituents are the same or differenthalogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, amino, C₁ -C₄ alkylamino or C₁ -C₄dialkylamino. Typical phen(C₁ -C₄ )alkyl groups include benzyl,2-pheneth-1-yl, 3-phenprop-1-yl, 4-phenbut-1-yl, 1-pheneth-1-yl,2-phenprop-1-yl, 2-(4-halophenyl)eth-1-yl, 4-halobenzyl, and the like.

The term "alkoxy" means any of methoxy, ethoxy, n-propoxy, isopropoxyand the like. The term "halogen" and "halo" means any of fluoro, chloro,bromo, and iodo. The term "alkylthio" means any of methylthio,ethylthio, n-propylthio, isopropylthio and the like.

The term "amido" means an aminocarbonyl (--C(O)NH₂) group. The term"alkylamino" means a group --NH(C₁ -C₄ alkyl) and the term "alkylamido"means a group --C(O)NH(C₁ -C₄ alkyl). Where a "C₁ -C₄ dialkylamino"(--N(C₁ -C₄ alkyl)₂) or "C₁ -C₄ dialkylamido" (--C(O)N(C₁ -C₄alkyl)₂)substituent is indicated, each alkyl group, independently, hasone to four carbon atoms.

The term "alkylsulfonyl" means a group --S(O)(alkyl) where the alkylgroup has the stated number of carbon atoms. Similarly, the term"alkylsulfonyl" means a group --SO₂ (alkyl) where the alkyl group hasthe stated number of carbon atoms. The term "alkylsulfonylamino" means agroup --NHSO₂ (C₁ -C₄ alkyl). The term "aminosulfonyl" means a group--SO₂ NH₂ and the term "alkylaminosulfonyl" means a group --SO₂ NH(C₁-C₄ alkyl ) .

The octahydrobenzo[f]quinolinones of the present invention are thosecompounds of formula I where R¹, R³, R⁴ and R⁵ are hydrogen.Correspondingly, the hexahydrobenzo[f]quinolinones of the presentinvention are those compounds of formula I having two less protons, asdescribed in the definitions for formula I.

The compounds of the present invention possess at least one asymmetriccarbon represented by the carbon atom labeled with an asterisk inFormula Ia, below. ##STR4##

The compounds of the present invention also exist as individual cis-dand cis-1-stereoisomers as well as trans-d-and trans-1-stereoisomers andmixtures of such isomers. The two cis and two trans configurations areshown below in Formula Ib-Ie. ##STR5## Accordingly, the compounds of thepresent invention include not only mixtures of two or more of suchindividual isomers but also an individual isomer.

In addition, further diastereomers exist depending upon the R², Z and Z¹substituents. The compounds of the present invention include mixtures oftwo or more diastereomers, and the individual isomers.

The following compounds illustrate compounds contemplated within thescope of Formula I:

cis-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-iodo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8,9-dichloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8,9-dichloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-fluoro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-fluoro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-fluoro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-ethoxycarbonylethenediyl-4-methyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-ethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-methoxy-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-ethoxycarbonylethanediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-methoxycarbonylethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-carboxyethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-t-butylaminocarbonylethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-2-(α-methyl)-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-2-(β-methyl)-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-t-butyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-t-butyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

cis-dl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-9-nitro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-9-nitro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-9-amino-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-9-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-3,4,4a,5,6,10b-hexahydrobenzo f]quinolin-3-one;

dl-8-chloro-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one;

trans-dl-8-bromo-4-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-4-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one;

dl-8-chloro-4-methyl-2,3,4,4a,5,6hexahydrobenzo[f]quinolin-3-one;

trans-dl-8-chloro-2-(α-methyl)-4-methyl-1,2,3,4,4a,10b-hexahydrobenzo[f]quinolin-3-one;

trans-dl-8-t-butylaminocarbonylethanediyl-4-methyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-phenyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-vinyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

trans-dl-8-ethoxycarbonyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one;

Preferred compounds of the present invention are those of Formula Iwhere:

R is hydrogen or C₁ -C₄ alkyl;

Z and Z¹ are indepedently hydrogen or methyl;

Y is hydrogen or methyl, and is in a trans configuration in relation tothe 4a position hydrogen;

R¹, R³, R⁴ and R⁵ are hydrogen;

R² is hydrogen or methyl;

n is 1 or 2;

X is halogen, CF₃, C₁ -C₆ alkyl, C₁ -C₄ alkoxy or --AR--R⁶ where A is C₁-C₄ alkylene and R⁶ is C₁ -C₄ alkoxycarbonyl; or a pharmaceuticallyacceptable salt thereof; provided that

(b) when R is hydrogen, methyl or ethyl, X is other than hydrogen ormethoxy; and

(c) when R is methyl, R² is other than methyl.

Most preferred compounds of the present invention are those of Formula Iwhere

R is hydrogen or methyl;

Z and Z¹ are both hydrogen or methyl;

Y is hydrogen or methyl, and is in a trans configuration in relation tothe 4a position hydrogen;

R¹, R³, R⁴ and R⁵ are hydrogen;

R² is hydrogen or methyl;

n is 1 or 2;

X is halogen, CF₃, or C₁ -C₄ alkyl; or a pharmaceutically acceptablesalt thereof; provided that

(c) when R is methyl, R² is other than methyl.

As mentioned above, the invention includes pharmaceutically acceptablesalts of the compounds defined by the above formula. Although generallyneutral, a particular compound of this invention can possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of nontoxic inorganic bases,and nontoxic inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Acids commonly employed to form acid addition salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acidssuch as p-toluene-sulfonic, methanesulfonic acid, oxalic acid,p-bromo-phenyl-sulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate,and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from nontoxic inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate. The potassium andsodium salt forms are particularly preferred.

The compounds of the present invention, or their precursors, areprepared using procedures known to those of ordinary skill in the art.Those compounds of the present -invention where Y is hydrogen arepreferably synthesized according to the following Scheme 1. ##STR6##

Where X, n, and R are as defined above for Formula I, R-EAA is anelectrophilic alkylating agent, and R^(a) and R^(b) are independentlyselected from hydrogen and C₁ -C₄ alkyl, or may be taken together withthe nitrogen atom to afford a 5-7 membered heterocyclic group which mayalso include an oxygen atom, provided that both R^(a) and R^(b) cannotbe hydrogen at the same time.

As depicted in Synthetic Scheme 1, the Δ4_(a) -10_(b)hexahydrobenzo[f]quinolinones represent the intermediates which, uponreduction of the double bond, affords compounds of this invention and/orcompounds useful as intermediates for the preparation of compounds ofthis invention.

The hexahydrobenzo[f]quinolinones are prepared from an unsubstituted orappropriately ring-substituted phenacetyl chloride. The phenacetylchloride is commercially available or is prepared by procedureswell-known to those skilled in the art. Typically, suitably substitutedphenylacetic acid is reacted with thionyl chloride, phosphoroustrichloride, oxalyl chloride, or phosphorous pentachloride, preferablythionyl chloride, under conditions known to those skilled in the art, toafford the corresponding phenacetyl chloride.

By a Friedel-Crafts acylation reaction of the phenacetyl chloride withethylene in the presence of a Lewis acid catalyst and in an inert orsubstantially inert solvent or mixture of solvents, ring closure iseffected to afford a 2-tetralone. Suitable Lewis acid catalysts includeAlBr₃, AlCl₃, GaCl₃, FeCl₃, SbCl₅, ZrCl₄, SnCl₄, BCl₃, BF₃, SbCl₃, andthe like, preferably AlCl₃. Solvents useful for this reaction includecarbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane,nitrobenzene, and the like, preferably methylene chloride. Activation ofphenacetyl chloride with the Lewis acid is carried out at temperaturesof from about -78° C. to about 25° C.

Addition of ethylene is exothermic in nature and temperatures from about-78° C. to about 30° C. are generally employed using standard coolingprocedures.

The 2-tetralone reaction product is then aminated with a primary orsecondary amine, preferably pyrrolidine, in an inert or substantiallyinert solvent or mixture of solvents to afford the correspondingenamine. In the case of a primary amine, this may be accompanied by theimine tautomer. The reaction is driven to completion by the removal ofwater which may be accomplished at elevated temperatures of from about80°-110° C. using a suitable solvent azeotrope or at about roomtemperature through the use of a suitable dehydrating agent such asmolecular sieves or magnesium sulfate. Suitable solvents are aproticorganic solvents such as benzene, toluene, THF, CH₂ Cl₂ and ethylacetate.

The enamine reaction product is then reacted with acrylamide in thepresence of an acid and in the presence or absence of an inert orsubstantially inert solvent or mixture of solvents to afford ahexahydro-2-(1H)-benzo[f]quinolinone. Acids useful in this reactioninclude strong organic or mineral acids, preferably B-toluene sulfonicacid (pTSA). Although the reaction can be carried out in a solvent,preferably no solvent is used. The reaction is carried out attemperatures of from about 90° C. to about 130° C.

The hexahydro-2(1H)-benzo[f]quinolinone may then be reduced to thecorresponding octahydrobenzo[f]quinolinones of the present invention.The octahydrobenzo[f]quinolines may then be N-alkylated to affordfurther compounds of the present invention.

Alternatively, the hexahydro-2(1H)-benzo[f]quinolinones may first be N-alkylated and then reduced to the correspondingN-alkyl-octahydrobenzo[f]quinolin-(3)-ones of the present invention.

Reduction is carried out by reacting the hexahydrobenzo[f]quinolinone orN-alkyl-hexahydrobenzo[f]quinolinone with an appropriate reducing agentin an inert or substantially inert solvent or mixture of solvents.Suitable reducing agents include hydrogenation over a metal catalyst,and hydride transfer reagents such as ammonium formate over a metalcatalyst, preferably triethylsilane/trifluoroacetic acid. Usefulsolvents include inert or substantially inert organic solvents,preferably methylene chloride. Temperatures of from about 0° C. to about60° C. are employed, preferably at about 25° C.

The N-alkylation is carried out by reacting thehexahydrobenzo[f]quinolinone or octahydrobenzo[f]quinolinone with anelectrophilic alkylating agent, R-EAA where R is as defined above forFormula I, in the presence of a base, in an inert or substantially inertsolvent or mixture of solvents. For this reaction, EAA is preferablyiodo. The base is generally a metal hydride, metal amide or metalalkoxide, preferably sodium hydride. Generally, this reaction is carriedout at temperatures of from about -30° C. to about solvent reflux.

Those compounds of the present invention where Y is methyl arepreferably synthesized according to the following Scheme 2. ##STR7##

where X, n, and R as defined above for Formula I, and R^(a), R^(b) andR-EAA are as defined above for Scheme 1.

As depicted above in Synthetic Scheme 2, the4a-methyl-hexahydrobenzo[f]quinolin-2(1H)-one are the intermediateswhich are reduced to afford the compounds of the present inventionand/or compounds useful as intermediates for the preparation ofcompounds of this invention.

An enamine is prepared by the procedures depicted in Schemes 1 and 2 anddescribed above for Synthetic Scheme 1. The enamine is alkylated byreaction with an electrophic alkylating agent, preferably methyl iodide,in an inert or substantially inert solvent or mixture of solvents.Temperatures for this reaction are generally from about 0° C. to about60° C. The reaction mixture is then subjected to hydrolysis with aqueousacid, preferably a mixture of sodium acetate, ethyl acetate and aceticacid. Temperatures of from about 0° C. to about 30° C. are employed inthis reaction to afford a 1-methyl-2-tetralone.

The 1-methyl-2-tetralone is then further reacted as depicted in Scheme 2using the reagents and procedures described above for Scheme 1, toafford the compounds of the present invention where Y is methyl.

Those compounds of the present invention where Z, Z¹, or both, are C₁-C₄ alkyl are prepared substantially according to the procedures inScheme 1 and Scheme 2 except that during the Friedel-Crafts ring closurereaction of phenacetyl chloride, an appropriate alkene, is used, ratherthan the ethylene shown in both Schemes 1 and 2. Examples of suitablealkenes for use in this reaction include propylene, 1-butene, 2-butene,isobutylene, 3,3-dimethyl-1-butene, 2-pentene, 4-methyl-2-pentene,3-methyl-1-butene, 2-methyl-2-butene, 2,3-di-methyl-2-butene and thelike.

Those compounds of Formula I where R² is C₁ -C₄ alkyl are prepared fromthe compounds afforded by Schemes 1 and 2, preferably where R is C₁ -C₄alkyl, unsubstituted or substituted phen(C₁ -C₄)alkyl as shown in thefollowing reaction Scheme 3: ##STR8##

where Y, X, n, R, and R² are as defined above for Formula I except R isnot hydrogen, and R² -EAA is an electrophilic alkylating agent where R2is as defined above for Scheme 1. The R-(alkyl or phenalkyl) compound isreacted with a base, such as a metal amide or metal alkoxide, preferablypotassium hexamethyldisilazide, in an inert or substantially inertsolvent or mixture of solvents at a temperature of from about -78° C. toabout 25° C. Alkylation is then effected by the addition of anappropriate electrophilic alkylating agent, preferably C₁ -C₄ alkyliodide, to afford the 2-(C₁ -C₄ alkyl) compounds of Formula I.

For those compounds of Formula I where R is H, the 4-position nitrogenatom is first blocked with a suitable amino protecting group such ast-butoxycarbonyl or benzyloxycarbonyl and then reacted as shown above inScheme 3. After alkylating at the 2-position, the 4-position nitrogenatom is deprotected. The protection and deprotection reactions arecarried out under standard conditions for such reactions.

An alternative method for preparing those compounds of the presentinvention where Y is methyl is shown below in Scheme 4. ##STR9## whereR, X and n are as defined above for Formula I.

Another aspect of this invention pertains to a particular method forproducing optically active isomers of the compounds of this invention.As depicted above in Scheme 4, a 1-methyl-2-tetralone is reacted with achiral amine, such as preferably 1-phenylethylamine in an inert orsubstantially inert solvent or mixture of solvents to afford thecorresponding enamine. If a primary chiral amine is used, the enaminemay be afforded by way of the imine tautomer. The reaction is driven bythe removal of water which may be accomplished at elevated temperaturesof from about 80° C. to about 110° C. using a suitable solvent azeotropeor at about room temperature through the use of a suitable dehydratingagent such as molecular sieves or magnesium sulfate.

The enamine is then reacted with a suitable alpha, beta-unsaturatedcarbonyl compound preferably methylvinyl ketone in a Michael additionreaction, followed by hydrolysis with a mild aqueous acid to afford a5,6,7,8,9,10-hexahydro-8-hydroxy-5,8-dimethyl-5,9-methanobenzocyclooctan-11-one.This reaction is carried out in an ethereal solvent such astetrahydrofuran (THF), dioxane or the like under an inert atmosphere,such as argon or nitrogen, at a temperature of from about 10° C. toabout 50° C., preferably at about room temperature. Generally, fromabout stoichiometric amounts of reactants to an excess of the alpha,beta-unsaturated carbonyl compound are employed in this reaction, andpreferably an excess of the alpha, beta-unsaturated carbonyl reactant.Suitable acids include organic carboxytic acids and perchloric acid andpreferably acetic acid.

The methanobenzocyclooctan-11-one is treated with an acidic or basiccatalyst, preferably sodium or potassium ethoxide, in a protic solvent,preferably ethanol, at reflux to afford a2,3,4,4a,9,10-hexahydro-4a-methyl-phenanthren-2-one.

The phenanthren-2-one is oxidatively cleaved with a suitable oxidizingagent such as ozone, KMnO₄, CrO₃ or RuO₄, preferably Rutheniumtetraoxide, in an inert or substantially inert solvent or mixture ofsolvents at from about -78° C. to about 100° C., preferably at fromabout -10° C. to about 10° C. to afford ab-[1-methyl-1-(2-oxo-1,2,3,4-tetrahydronaphthyl)] propionic acid.Generally, the solvent will be an inert solvent or mixture of solventsand preferably the solvent will be a mixture of 2 parts carbontetrachloride, 3 parts acetonitrile and 2 parts water.

The propionic acid is reacted with ammonia or a primary amine (NH Rwhere R is as defined above for Formula I) in an inert or substantiallyinert solvent or mixture of solvents preferably 2-propanol, at atemperature of from about 95° C. to about 200° C., preferably from about165° C. to about 180° C. to afford a10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one of the presentinvention. Preferably this reaction is carried out in the relativeabsence of oxidizing agents, such as air in, for example, a sealedreactor or the like.

The hexahydrobenzo[f]quinolinone may be reduced to the correspondingoctahydro compound of the present invention by substantially the sameprocedures described above in Schemes 1 and 2.

By following the procedures depicted in Scheme 4 and as described above,the substantially pure optically active isomers of the compounds of thisinvention where Y is methyl are afforded.

The preferred asymmetric synthesis of the individual enantiomercompounds of Formula I, or their precursors, is carried out by reactingan enamine of the formula ##STR10## with an acryloyl derivative of theformula ##STR11## where Y, X, R² and n are as defined above for FormulaI; G is a leaving group such as chlorine, bromine, fluorine, iodine,toluene sulfonate, methane sulfonate and symmetrical or unsymmetricalanhydrides; and R^(c) is 1-phenethyl. The 1-phenethyl substituent issubsequently cleaved using trifluoroacetic acid. It will be appreciatedthat the --COG radical of the acryloyl derivative is an activated formof --COOH, which can be activated in other ways such as active esters,mixed anhydrides and the like.

The process conditions for carrying out the preferred individual isomersynthesis of Schemes are extremely mild. In most instances, it will befound that excellent yields are obtained in short periods of time attemperatures in the range of ambient. For example, temperatures fromabout 0° to about 150° are used, and reaction times in the range of fromabout a few minutes to, at maximum, a few hours, are sufficient. Thereaction medium is preferably a biphasic mixture of a convenient organicsolvent and an aqueous solution of a mild base. Useful solvents include,for example, haloalkanes, ethers including tetrahydrofuran, and nitrilesincluding acetonitrile. Preferred mild bases are alkali metal carbonatesand bicarbonates; more highly basic reagents such as alkali and alkalineearth metal hydroxides and the like may be used in some cases, but thebicarbonates are typically preferred. The process may also be performedwithout a base if desired.

The products of this synthesis are readily isolated by conventionalprocess steps. The use of this process provides a particularly cleansynthesis of single-isomer forms of the reaction product.

It will be understood that the products of the present process may beused as such to take advantage of their biological activity, or they maybe used as intermediates in additional processes to prepare activecompounds within the scope of Formula I.

Those hexahydrobenzo[f]quinolin-3-ones of Formula I having a Δ¹ or Δ5carbon-carbon double bond are prepared from the correspondingoctahydrobenzo[f]quinolin-3-ones by addition/elimination reactions. Theoctahydrobenzo[f]quinolin-3-one is reacted with a sulfur or selenoelectrophile in the presence of a base, in an aprotic solvent. The baseis generally a metal hydride or metal amide, preferably a metal hydridesuch as sodium hydride. Although generally one equivalent of base isadded for each equivalent of octahydrobenzo[f]quinoline, for thosecompounds where R is hydrogen, a second equivalent of base is added.Temperatures for this reaction are from about 20° C. to about the refluxtemperature of the solvent. The addition reactant is a sulfur or selenoelectrophile and is carried out at a temperature of from about -50° C.to about -100° C. Suitable sulfur electrophiles are substantiallysimilar to sulfur groups useful in nucelophilic substitution and areknown to those skilled in the art, Patai, "The Chemistry of the ThiolGroup," Wiley, N.Y. (1974); Reid, "Organic Chemistry of BivalentSulfur", Chemical Publishing Company, New York (1958, 1963); Kharasch,"Organic Sulfur Compounds," Perganon, N.Y. (1961).

Suitable seleno compounds include phenylselenenyl chloride,phenylselenenyl bromide, N-(phenylseleno)phthalimide, diphenyldiselenide, benzeneseleninic anhydride and selenoxides. Specificconditions for a particular seleno reactant are well known or readilyascertained by one skilled in the art, Clive, Tetrahedron, 34, 1049-1132(1978); Aldrichimica Acta, 11, 43-49 (1978); and Miyoshi, et al.,Tetrahedron Lett., 23, 4813 (1982).

The elimination reaction is generally carried out under oxidativeconditions in an aprotic solvent. March, "Advanced Organic Chemistry",3rd Ed., p. 912-914, Wiley-Interscience, New York (1985).

The Δ^(10b) compounds of the present invention are obtained byrearrangement (isomerization) from the corresponding Δ¹ compounds when Yis hydrogen. This reaction is carried out in an aprotic solvent in thepresence of an acid or base catalyst, under conditions well known orreadily ascertained by one skilled in the art.

The Δ^(4a) compounds of the present invention are prepared asintermediates by the procedures described above in Scheme 4 and areisolated, rather than reduced to the correspondingoctahydrobenzo[f]quinolin-3-one.

The optically active isomers of the racemates of the invention are alsoconsidered part of this invention. Such optically active isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Thisresolution can be carried out by derivatization with a chiral reagentfollowed by chromatography or by repeated crystallization. Removal ofthe chiral auxiliary by standard methods affords substantially opticallypure isomers of the compounds of the present invention or theirprecursors. Further details regarding resolutions can be obtained inJacques, et al., Enantiomers, Racemates, and Resolutions, John Wiley &Sons, 1981.

A further aspect of the present invention and the preferred method ofresolving racemates of those compounds of Formula I where R is hydrogenor C₁ -C₄ alkyl; Z and Z¹ are independently selected from hydrogen andC₁ -C₄ alkyl; Y is hydrogen; R¹, R², R³, R⁴ and R⁵ are all hydrogen; nis 1 or 2; and X is hydrogen, halogen, NO₂, CF₃, C₁ -C₆ alkyl, C₁ -C₄alkoxy, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino, mercapto, or C₁-C₆ alkylthio;

into their component optical isomers comprising essentially the stepsof:

(a) contacting a methanol solution of a racemate with a strong acid toafford a1-(2-methoxycarbonylethyl)-2-(amino)-1,2,3,4-tetrahydronaphthalene;

(b) contacting said tetrahydronaphthalene from (a) with a methanolsolution of an optically active di-p-toluoyltartaric acid to afford acorresponding tetrahydronaphthalene salt; and

(c) treating said salt from (b) with a base to afford an opticallyactive isomer.

As a further aspect of the present invention, in addition to the processfor resolving a racemic mixture of those compounds of formula Ispecified above, there is provided the di-p-toluoyl-(D)- and(L-)tartaric acid salts of 1-(2-methoxycarbonylethyl)-2-(amino or C₁ -C₄alkylamino)-1,2,3,4-tetrahydronaphthalene.

This resolution is accomplished by dissolving a racemic mixture ofoptically active isomers as defined above in methanol, and contactingsaid solution with a strong acid to afford a1-(2-methoxycarbonylethyl)-2-(amino or C₁ -C₄alkylamino)-1,2,3,4-tetrahydronaphthalene intermediate. Suitable strongacids include inorganic acids such as hydrochloric acid , nitric acid,phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid andthe like, as well as organic acids, such as aromatic sulfonic acids andthe like. Inorganic acids are preferred and sulfuric acid is mostpreferred. The tetrahydronaphthalene intermediate is then contacted witha methanol solution of an optically active di-p-toluoyltartaric acid toafford a corresponding tetrahydronaphthalene salt. Where the (+)enantiomer is desired, (-)-di-p-toluoyl-L-tartaric acid is used.Correspondingly, where the (-) isomer is desired(+)-di-p-toluoyl-D-tartaric acid is used.

The salt formed can be separated from the mixture by conventionalmethods. For example, the separated salt can be treated in an aqueousmedium with a base to form the free amine which can be extracted fromthe aqueous phase with a water immiscible solvent. The free amine may beheated to from about 35° C. to about 120° C. to recyclize and afford thedesired octahydrobenzo[f]quinolinone, depending upon the extractingsolvent used.

Suitable bases for use in the above process are generally weak bases,preferably sodium or potassium carbonate or bicarbonate and mostpreferably sodium bicarbonate. Suitable water immiscible solventsinclude methylene chloride, toluene, ethyl acetate, methyl tert-butylether, and diethyl ether, preferably methylene chloride.

One skilled in the art will appreciate that the selectivecrystallization of one diastereomer from an organic solution is alsoaffected by concentration. A relatively low concentration provides purediastereomer of generally higher purity but lower yield, while theutilization of a higher concentration of racemate and resolving agentwill normally provide higher yields of solid, many times at the expenseof optical purity.

The compounds employed as initial starting materials in the synthesis ofthe compounds of this invention are well known and, to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed by those of ordinary skill in the art.

The pharmaceutically acceptable salts of the invention are typicallyformed by reacting an octahydrobenzo[f]quinolinone of this inventionwhich possesses suitable acidic or basic functionality with an equimolaror excess amount of acid or base. The reactants are generally combinedin a mutual solvent such as diethyl ether or benzene, for acid additionsalts, or water or alcohols for base addition salts, and the saltnormally precipitates out of solution within about one hour to 10 days,and can be isolated by filtration or other conventional means.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates areincluded as compounds of this invention.

The following Examples further illustrate the compounds of the presentinvention and methods for their synthesis. The Examples are not intendedto be limiting to the scope of the invention in any respect and shouldnot be so construed.

EXAMPLE 1

Preparation of cis-dl and trans-dl 8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A. 4-bromophenylacetyl chloride.

To a 250 ml round bottom flask fitted with a magnetic stirrer was added4-bromophenylacetic acid (100.0 g; 0.465 mol) and 100 ml of thionylchloride (163.1 g; 1.37 mol). The resulting slurry was stirred at roomtemperature for 22.5 hrs. The excess thionyl chloride was evaporatedunder vacuum to afford 108.5 g of the subtitle compound as a brownliquid.

B. 6-bromo-2-tetralone.

To a cold (-78° C.; dry ice/isopropanol bath) suspension of AlCl₃ (125g; 0.94 mol) in 1,400 ml CH₂ Cl₂ was added the acid chloride afforded inStep A (108.5 g; 0.47 mol) dissolved in 400 ml of dry CH₂ Cl₂ withstirring over one hour. The dry ice/isopropanol bath was removed and thesolution was allowed to warm to -10° C. Ethylene was then bubbled intothe flask with vigorous stirring. The reaction warmed-exothermically to20° C. at which time the addition of ethylene was stopped. The mixturewas stirred at room temperature for three hours, then it was cooled to0° C. and ice added until no further exotherm was observed. The reactionmixture was diluted with 1L of ice cold water and stirred until allsolids dissolved. The resulting layers were separated and the organiclayer washed twice with one liter portions of 1 N HCl and then once with1L of saturated Na₂ HCO₄. The organic layer was dried over Na₂ SO₄ andconcentrated under a vacuum to afford a pale yellow crystalline solid.

The 6-bromo-2-tetralone crystals were taken up in a minimum amount ofether. Hexane was cautiously added until the solution just started toturn cloudy. The mixture was refrigerated for four hours, filtered, andwashed with cold hexanes to afford 75.6 g of the subtitle compound as apale yellow crystalline solid (71% yield) melting point 71°-73° C.

C. 2-pyrrolidinyl-6-bromo-3,4-dihydronaphthalene.

To a 250 ml round bottomed flask was added 5.00 g (22.21 mmol) of the6-bromotetralone afforded above in Step B; 70 ml of dry toluene and 3.1g (3.7 ml) of pyrrolidine. The flask was equipped with a Dean-Starktrap, a condenser, a nitrogen inlet tube and a magnetic stirrer and thereaction refluxed for four hours. The solvent was evaporated undervacuum to afford 6.02 g (97.4% ) of the subtitle compound as a browncrystalline material which was used without further purification.

D. 8-bromo-1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one.

The enamine (2.15 g; 7.73 mmol) from Step C, acrylamide (1.10 g; 15.46mmol) and 100 mg of p-toluene sulfonic acid (pTSA) were mixed thoroughlyin a mortar and pestle. The mixture was transferred to a 250 ml roundbottomed flask equipped with a magnetic stirrer and nitrogen inlet.Using a mineral oil bath, the mixture was heated to 89° C. at whichpoint the stirred mixture turned black and melted. The temperature washeld constant at 89° C. for 1.5 hours. At this point the temperature wasincreased to 130° C. and was held there for 0.5 hours. The oil bath wasremoved and 60 ml of water was cautiously added. The resulting murkygray material was mixed thoroughly with a spatula and 80 ml of water wasadded to aid in filtration. Brown crystals (1.02 grams) were afforded bythe filtration. The crystals were taken up in CHCl₃ and activated carbonwas added. This mixture was stirred for 15 minutes, filtered, andevaporated under vacuum. The residue was taken up in a minimum amount ofethyl acetate with the help of a steam bath, and transferred to anErlenmeyer flask, equipped with a magnetic stirring bar and sub-mergedin a dry ice/acetone bath with stirring to afford the subtitle compoundas a white crystalline solid (melting point 215-217 decomp.). 1st crop940 mg; 2nd crop 175 mg (55% yield).

E. 8-bromo-4-methyl-1,2,3,4,5,6-hexahydrobenzo[f]quinolinone-3-one.

By substantially following the procedures described above 5.17 g of the8-bromo-1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one was obtained. Thehexahydrobenzoquinolinone (5.17 g; 19.6 mmol) was dissolved in 60 ml ofdry diethyl ether in a 250 ml round bottomed flask. To the solution wasadded 1.2 g of sodium hydride (60% dispersion in mineral oil). The flaskwas fitted to a reflux condenser with a stirring bar and the mixturerefluxed for 2 hours. The mixture was then cooled to room temperatureand 7.35 ml of methyl iodide was added. After addition, the reactionmixture was refluxed for an additional 3 hours. After cooling, thereaction mixture was quenched by the cautious addition of 5 ml of water.The mixture was then concentrated under vacuum affording a pale solidcrystals which was taken up in a ethyl acetate/water mixture and theresulting layers separated. The organic layer was washed twice withwater and once with brine and then dried over MgSO₄ and evaporated undervacuum to afford 5.22 g of a yellow crystalline solid. The solid wasrecrystallized from acetone to afford 3.55 g (62%) of the subtitlecompound as a pale yellow solid. Melting point 126°-128° C.

F. 8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one.

To a solution of the hexahydrobenzoquinolinone prepared above in Step E(1.17 g; 4.0 mmol) in 10 ml of dry dichloromethane was addedtriethylsilane (1.37 g; 11.8 mmol). The resulting mixture was stirredfor 10 minutes at room temperature. The reaction mixture was cooled inan ice bath and trifluoroacetic acid (5 ml) was added. The resultingmixture was stirred at room temperature for four days. The reactionmixture was concentrated under vacuum. The oil residue was taken up inCH₂ Cl₂ and washed with saturated NaHCO₃. The organic layer was driedover sodium sulfate and concentrated under vacuum to afford an orangeoil. Flash chromatography on SiO₂ (elution with 0.5% methanol/CH₂ Cl₂)gave 1.14 g of a light brown oil. Proton NMR spectroscopy revealed theratio of trans:cis to be 3.2:1.

G. Cis-dl and trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The cis and trans isomers were separated by HPLC on SiO₂ (in hexane withincreasing gradient of ethyl acetate). The trans isomer (Example 1A)came off first affording 631 mg; and the cis (Example 1B) isomer cameoff second affording 192 mg. The trans isomer was recrystallized fromdiethyl ether/hexanes to afford 176 mg; melting point 103°-104.5° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Trans (1A)                                                                    Calculated:                                                                              57.16        5.48   4.76                                           Found:     57.57        5.53   4.64                                           Cis (1B)                                                                      Calculated:                                                                              57.16        5.48   4.76                                           Found:     57.46        5.67   4.59                                           ______________________________________                                    

EXAMPLE 2

Preparation of trans-dl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compound 8-bromo-1,2,3,4,5,6-hexahydrobenzo[f]-quinolin-3-one wasprepared according to the procedures described in Example 1, Steps A, B,C, and D.

The title compound was prepared according to the procedure describedabove in Example 1, Step F, to afford 84 mg of a white, crystallinematerial (29% yield) following recrystallization from ethyl acetate;melting point of 252°-254° C. decomp.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              55.73        5.04   5.00                                           Found:     55.47        5.07   4.89                                           ______________________________________                                    

EXAMPLE 3

Preparation oftrans-dl-8-iodo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one.

The compoundtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was prepared according to the procedures described in Example 1,Steps A, B, C, D, E, F, and G.

To a stirred solution of the trans isomer (475 mg; 1.614 mmol) in 3.5 mlof dry dioxane was added hexamethylditin and 54 mg (3 mol %) oftetrakis(triphenylphosphine)palladium. The reaction mixture was refluxedfor 2.5 hours, cooled to room temperature, filtered through diatomaceousearth (Celite®) and concentrated to afford a pale yellow oil. Thematerial was further concentrated under a high vacuum overnight at roomtemperature to afford 677 mg of the corresponding 8-trimethyltincompound as a pale yellow oil which was used below without furtherpurification.

To a cold (-78° C.) solution of the 8-trimethyltin compound preparedabove in 5.0 ml CH₂ Cl₂ was added 1.6 ml of 1.0 M iodine monochloridedropwise. The reaction mixture was allowed to warm to room temperatureover 1.5 hours. The mixture was quenched with 1 ml of water, filtered,and the volatiles evaporated under vacuum to afford a black oilymaterial. The black oily material was flash chromatographed on SiO₂(eluted with 5% isopropanol/CH₂ Cl₂) to afford a yellow crystallinesubstance, which was recrystallized from ethyl acetate/hexanes to affordthe title compound 141 mg (86% yield) as an off-white crystallinematerial; melting point:103°-104.5° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              49.28        4.73   4.11                                           Found:     49.48        4.72   3.96                                           ______________________________________                                    

EXAMPLE 4

Preparation oftrans-dl-8,9-dichloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared employing 3,4-dichlorophenylacetic acidas the starting material according to the procedures described above inExample 1, Steps A, B, C, D, and F, to afford 567 mg of the titlecompound as an off-white highly crystalline material. Melting point267°-268° C. decomp.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              57.80        4.85   5.18                                           Found:     58.22        5.04   5.18                                           ______________________________________                                    

EXAMPLE 5

Preparation oftrans-dl-8,9-dichloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

Following the procedures described above in Example 1, Steps A, B, C, D,and F, followed by recrystallization from ethyl acetatetrans-dl-8,9-di-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared using 3,4-dichlorophenylacetic acid as the startingmaterial.

The title compound was prepared fromtrans-dl-8,9-dichlorooctahydrobenzo[f]quinolinone according to theprocedures described in Example 1, Step E to afford 117 mg (35% yield)of a beige solid material. Melting point 168°-169° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              59.17        5.32   4.93                                           Found:     59.45        5.08   4.83                                           ______________________________________                                    

EXAMPLE 6

Preparation oftrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound, along with the cis-dl- isomer (Example 7), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-chlorophenylacetic acid as the starting material.Separation according to Example 1, Step G, afford 500 mg of the titlecompound. Melting point 82° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              67.33        6.46   5.61                                           Found:     67.60        6.63   5.67                                           ______________________________________                                    

EXAMPLE 7

Preparation ofcis-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the trans-dl- isomer (Example 6), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-chlorophenylacetic acid as the starting material.Separation according to Example 1, Step G, afforded 200 mg of the titlecompound as an oil.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              67.33        6.46   5.61                                           Found:     67.57        6.82   5.70                                           ______________________________________                                    

EXAMPLE 8

Preparation oftrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the cis-dl- isomer (Example 9), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-tolylacetic acid as the starting material.Separation according to Example 1, Step G, afforded 400 mg of the titlecompound. Melting point 115°-116° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              78.56        8.35   6.11                                           Found:     78.79        8.32   6.11                                           ______________________________________                                    

EXAMPLE 9

Preparation of cis-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the trans-dl- isomer Example 8), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-tolylacetic acid as the starting material.Separation according to Example 1, Step G, afforded 290 mg of the titlecompound. Melting point 78° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              78.56        8.35   6.11                                           Found:     78.26        8.56   5.87                                           ______________________________________                                    

EXAMPLE 10

Preparation oftrans-dl-8-fluoro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the cis-dl- isomer (Example 11) wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-fluorophenylacetic acid as the starting material.Separation according to Example 1, Step G, afforded 244 mg of the titlecompound. Melting point 108°-109° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              72.80        6.91   6.00                                           Found:     72.07        6.89   6.09                                           ______________________________________                                    

EXAMPLE 11

Preparation ofcis-dl-8-fluoro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the trans-dl- isomer (Example 10), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using p-fluorophenylacetic acid as the starting material.Separation according to Example 1, Step G, afforded 130 mg of the titlecompound. Melting point 136°-137° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              72.08        6.91   6.00                                           Found:     72.30        7.04   6.06                                           ______________________________________                                    

EXAMPLE 12

Preparation oftrans-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the cis-dl- isomer (Example 13), wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using phenylacetic acid as the starting material.Separation according to Example 1, Step G afforded 200 mg of the titlecompound. Melting point 128°-129° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              78.10        7.96   6.51                                           Found:     77.87        7.85   6.46                                           ______________________________________                                    

EXAMPLE 13

Preparation ofcis-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound along with the trans- dl-isomer (Example 12) wasprepared according to the procedures described in Example 1, Steps A, B,C, D, E, and F using phenylacetic acid as the starting material.Separation according to Example 1, Step G, afforded the title compound.Melting point 129°-130° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              78.10        7.96   6.51                                           Found:     78.32        7.04   6.58                                           ______________________________________                                    

EXAMPLE 14

Preparation ofcis-dl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compound 1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one was preparedaccording to the procedures described in Example 1, Steps A, B, C, and Dusing phenylacetic acid as the starting material.

To 94 ml of acetic acid was added1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one (3 g; 15 mmol) and 3 g of 5%palladium on activated carbon. The mixture was allowed to stand at roomtemperature for three days at an initial hydrogen pressure of 60 psi.The catalyst was removed by filtration. The filtrate was diluted withethyl acetate and made basic with saturated NaHCO₃. The resulting layerswere separated and the organic layer dried over MgSO₄ and concentrated,to afford 1.4 g (46% yield) of the title compound. Melting point178°-179° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              77.58        7.51   6.96                                           Found:     77.88        7.52   7.05                                           ______________________________________                                    

EXAMPLE 15

Preparation oftrans-dl-8-fluoro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, F, and G using p-fluorophenylacetic acid asthe starting material to afford 14.2 mg of the title compound. Meltingpoint 262°-263° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              71.21        6.44   6.39                                           Found:     71.17        6.48   6.29                                           ______________________________________                                    

EXAMPLE 16

Preparation oftrans-dl-8-ethoxycarbonyl-ethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 1, StepsA, B, C, D, E, F, and G. This compound (1.52 g; 5.17 mmol) and palladium(II) acetate (12 mg; 0.052 mmol), tri-(o-tolyl)phosphine (64 mg; 0.28mmol), ethyl acrylate (647 mg; 6.46 mmol) and triethylamine (2.8 ml)were combined in a thick-walled tube equipped with a magnetic, non-stickTeflon® coated, stir bar. The reaction mixture was heated to 100° C. inthe sealed tube and maintained there overnight. After cooling, 1 N HClwas added and the green solid stirred gently with a spatula. The solidswere collected by filtration and dissolved in ethanol with heating. Thesolution was filtered through diatomaceous earth (Celite®) and washedseveral times with ethanol. The volatiles were evaporated under vacuumto afford a solid yellow residue. Recrystallization of the residue froma mixture of ethyl acetate/hexanes afforded 1.24 g of the title compoundas a fluffy yellow material (88% yield) . Melting point 115.5°-116.5° C.High resolution Mass Spec.:313.1659 C₁₉ H₂₃ NO₃.

EXAMPLE 17

Preparation oftrans-dl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, F, and G using p-chlorophenylacetic acid asthe starting material. Melting point 231°-232° C.

    ______________________________________                                        Elemental Analysis:                                                                    C          H      N                                                  ______________________________________                                        Calculated:                                                                              66.24        5.97   5.94                                           Found:     66.44        6.17   6.06                                           ______________________________________                                    

EXAMPLE 18

Preparation oftrans-dl-8-methoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, and F, followed by recrystallization fromethyl acetate using p-methoxyphenylacetic acid as the starting method toafford 198 mg (38%) of an off-white highly crystalline material. Meltingpoint 216°-217° C.

EXAMPLE 19

Preparation oftrans-dl-8-methoxy-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, F, recrystallization from ethyl acetate andthen E using p-methoxyphenylacetic acid as the starting material toafford 38 mg of a yellow powder. Melting point 102°-103° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              72.20         7.40   6.05                                          Found:     72.61         7.59   5.94                                          ______________________________________                                    

EXAMPLE 20

Preparation oftrans-dl-8-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, F, and G using p-tolylacetic acid as thestarting material. Melting point 226°-227° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.10         7.96   6.51                                          Found:     78.39         8.19   6.27                                          ______________________________________                                    

EXAMPLE 21

Preparation of trans-dl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 1, Steps A, B, C, D, and F using phenylacetic acid as thestarting material to afford 327 mg (30% yield) after fourrecrystallizations from ethyl acetate. Melting point 227°-228° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              77.58         7.58   6.96                                          Found:     77.29         7.74   6.99                                          ______________________________________                                    

EXAMPLE 22

Preparation oftrans-dl-8-ethoxycarbonylethanediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-ethoxycarbonylethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas prepared according to the procedures described in Example 16. Thiscompound (424 mg; 1.35 mmol) was combined with 50 mg of 5% palladium onactivated carbon in 50 ml of ethanol in a sealed reactor at roomtemperature under an initial pressure of 60 p.s.i. After four hours, thecatalyst is removed by filtration. The filtrate was concentrated undervacuum. The residue was subjected to flash chromatography on SiO₂ andelution with (5% methanol/CH₂ Cl₂ afforded 308 mg (72%) of the titlecompound as a light yellow oil which crystallized on standing. Meltingpoint 86°-88° C. High resolution Mass Spec.:315.1840 C₁₉ H₂₅ NO₃.

EXAMPLE 23

Preparation oftrans-dl-8-methoxycarbonyl-ethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 16, except that methyl acrylate was used rather than ethylacrylate, to afford 1.18 g (94% yield). Melting point 172°-174° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              72.22         7.07   4.68                                          Found:     71.97         7.87   4.72                                          ______________________________________                                    

EXAMPLE 24

Preparation oftrans-dl-8-carboxyethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-ethoxycarbonylethenediyl-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 16. To asolution of KOH (436 mg; 7.77 mmol) in a 3:1 (V:V) mixture of methanoland water was added the ethyl ester (1.22 g; 3.89 mmol). The reactionmixture was heated at reflux with stirring for one hour. The methanolwas removed under vacuum and the remaining mixture acidified with 5NHCl. A resulting white precipitate was collected by filtration andwashed with water. Recrystallization from ethanol afforded 741 mg (67%yield) of the title compound as a white crystalline material. Meltingpoint 311° C. decomp.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              71.56         6.71   4.91                                          Found:     71.82         6.57   4.88                                          ______________________________________                                    

EXAMPLE 25

Preparation oftrans-dl-8-t-butylaminocarbonylethenediyl-4-methyl-1,2,3,4,4a,5,6,10boctahydrobenzo[f]quinolin-3-one.

A.Trans-dl-8-(2-thiopyridylcarbonylethenediyl)-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-carboxyethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 24. Asuspension of this acid (1.99 g, 6.97 mmol), triphenylphosphine (3.66 g,13.95 mmol) and 2,2'-dithiodipyridine (3.07 g, 13.95 mmol) in 30 ml ofanhydrous toluene was stirred at room temperature overnight. Thereaction mixture was filtered and the precipitate washed with 100 ml ofdiethyl ether and dried to afford 2.2 g of the subtitled compound as apale yellow solid (81%).

B.Trans-dl-8-t-butylaminocarbonylethenediyl-4-methyl-1,2,3,a,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

To a stirred suspension of the thiopyridyl-ester afforded in step A,above, (440 mg; 1.13 mmol) in dry THF (11.0 ml) was addedtert-butylamine (0.95 ml; 9.04 mmol). The reaction mixture was stirredat room temperature for 24 hours. The mixture was filtered and thesolids washed with hexanes to afford 256 mg (66.5% yield) of the titlecompound. Melting point 243°-245° C. decomp.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              74.08         8.29   8.23                                          Found:     74.21         8.39   8.11                                          ______________________________________                                    

EXAMPLE 26

Preparation of trans-dl-8-chloro-2-(α andβ)-methyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

The compound trans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was prepared according to the proceduresdescribed in Example 6.

To a cold (-78° C.; dry ice/isopropanol bath) stirred solution oftrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(759 mg; 2.88 mmol) in 45 ml of dry THF was added 17.6 ml of 0.5 Mpotassium hexmethyldisilazide (1.1 equiv.; 8.81 mmol) in toluenedropwise. After the addition was complete, the reaction mixture wasstirred in the cold for an additional 45 minutes. An excess (5.0 equiv.)of methyl iodide (2.5 ml) was added to the reaction mixture. The coolingbath was removed and the reaction mixture allowed to warm to roomtemperature over 2 hours. The reaction was quenched by the cautiousaddition of water and the mixture transferred to a separatory funnel. Tothe mixture was added ethyl acetate and 1 N HCl and the layersseparated. The organic layer was washed with 1 N HCl, once withsaturated NaHCO₃ and then brine. The organic material was dried overMgSO₄ and evaporated under vacuum to afford 2.11 g of the title compoundas a yellow solid.

The α and β isomers were separated by HPLC on silica gel using 0-75%ethyl acetate/toluene (v:v) gradient to afford 414 mg of the α-isomer(Example 26A; melting point -167° C.) as a white solid and 199 mg of theβ isomer (Example 26B; melting point 82°-83° C.) as a colorless solid.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        α-isomer                                                                Calculated:                                                                              68.30         6.88   5.31                                          Found:     68.09         6.93   5.20                                          β-isomer                                                                 Calculated:                                                                              68.30         6.88   5.31                                          Found:     68.05         6.68   5.55                                          ______________________________________                                    

EXAMPLE 27

Preparation oftrans-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

4,4-dimethyl-6-bromo-2-tetralone was prepared according to theprocedures described in Example 1, Steps A and B with the exceptionsthat isobutylene was used in Step B rather than ethylene and that the1:1 mixture of 4,4-dimethyl and 3,3-dimethyl regioisomeric tetralonesobtained was separated by HPLC on silica gel using 0-7.5% ethylacetate/hexanes (v:v) gradient to give the desired4,4-dimethyl-6-bromo-2-tetralone. The title compound was prepared fromthis tetralone according to the procedures described in Example 1, StepsC, D, and F and then recrystallization from ethyl acetate to yield3.09.3 mg of a white solid. Melting point 281°-282° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              58.45         5.89   4.54                                          Found:     58.68         5.77   4.44                                          ______________________________________                                    

EXAMPLE 28

Preparation oftrans-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4a,5,6,10b-ocathydrobenzo[f]quinolin-3-one.

A mixture of trans andcis-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas obtained by concentration of the filtrates of the ethyl acetaterecrystallizations oftrans-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(Example 27). The title compound was prepared from this material alongwith the cis-dl-isomer (Example 29) using the procedures described inExample 1, Steps E and G to afford 67.2 mg of a white solid. Meltingpoint 133°-136° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              59.64         6.26   4.35                                          Found:     59.50         6.21   4.55                                          ______________________________________                                    

EXAMPLE 29

Preparation ofcis-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A mixture of trans andcis-dl-8-bromo-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas obtained by concentration of the filtrates of the ethyl acetaterecrystallizations oftrans-dl-8-bromo-6,6-dimethyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(Example 27). The title compound was prepared from this material alongwith the trans-dl-isomer (Example 28) using the procedures described inExample 1, Steps E and G to afford 67.2 mg of a white solid. Meltingpoint 177°-180° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              59.64         6.26   4.35                                          Found:     59.85         6.16   4.28                                          ______________________________________                                    

EXAMPLE 30

Preparation oftrans-dl-8-t-butyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A. 6-tert-butyl-2-naphthol.

A 2 L round bottomed flask was charged with freshly fused zinc chloride(45.0 g), β-naphthol (150.0 g; 1.04 mol) and hexanes (450 ml). Themixture was stirred vigorously while adding t-butyl chloride (150.0 g;1.62 mol) dropwise over 30 min. When the reaction mixture was graduallyheated to reflux, a solution was not obtained. The reaction mixture wascooled to room temperature and 100 ml of CH₂ Cl₂ was added. The reactionmixture was refluxed overnight, cooled and concentrated under vacuum toafford a white solid. The solid was refluxed with 1800 ml of 10% NaOH,filtered, and allowed to cool. The white sodium salt which precipitatedwas collected by filtration. The solid collected by filtration wasstirred with excess 5.0 M HCl and the resulting phenol was collected byfiltration and washed with 2 L of water. Recrystallization from heptaneafforded 30.67 g of the subtitle compound as a white solid.

B. 6-t-butyl-2-methoxynaphthalene.

To a 2 L round bottomed flask was added 6-t-butyl-2-naphthol (30.67 g;0.153 mmol) and 550 ml of 15% KOH in water. The solution was stirredwhile adding dimethyl sulfate (6.0 equiv.) dropwise over 30 min. Afterthe addition was complete, the mixture was allowed to stir for 2 hrs.The solids were collected on a filter and washed with water to afford28.97 g (88% yield) of the subtitle compound.

C. 6-t-butyl-2-tetralone.

To a stirred solution of 6-t-butyl-2-methoxynaphthalene (28.97 g; 0.135mmol) in 350 ml of anhydrous ethanol was added sodium spheres (36 g;11.5 equiv.) over 2 hrs. at a rate so as to maintain a gentle reflux.The viscous reaction mixture was stirred until all of the sodium haddissolved. The mixture was cooled and 140 ml of water was cautiouslyadded. Concentrated HCl (275 ml) was added and the reaction mixture wasrefluxed for 30 minutes. After cooling, the reaction mixture wasfiltered and the aqueous layer was extracted 3 times with toluene.Evaporation off the volatiles under vacuum afforded 28.1 g of a redviscous oil. The oil was taken up in 300 ml of diethyl ether and stirredwith 50 ml of saturated aqueous NaHSO₃ overnight. The resulting whiteprecipitate was collected by filtration and washed several times withhexanes. This material was partially dissolved in 500 ml of H₂ O and 200ml of diethyl ether was added. The mixture was vigorously stirred and300 ml of saturated aqueous Na₂ CO₃ added. The mixture was stirred forone hour, the layers were separated, and the aqueous layer was extracted3 times with diethyl ether. The combined organic layers were combined,washed with brine, dried over MgSO₄ and concentrated under vacuum toafford 5.74 g of the subtitle compound as an orange oil whichcrystallized slowly on standing.

D. 6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene.

To a stirred solution of 6-t-butyl-2-tetralone (5.74 g; 28.37 mmol) in100 ml of toluene was added 1.5 equiv. of pyrrolidine (3.56 ml; 42.56mmol). A 100 mg portion of p-toluenesulfonic acid was added and themixture was refluxed. The water eliminated during the reaction wascollected by a Dean Stark trap. After a reflux time of 3.5 hours,concentration of the volatiles under vacuum afforded 7.31 g of thesubtitle compound as a purple solid.

E. 8-t-butyl-1,2,3,4,5,6, -hexahydrobenzo[f]quinolin-3 -one.

To 6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene (7.25 g; 28.37 mmol)was added 3.0 equiv. of acrylamide (6.05 g; 85.11 mmol). The reactionmixture was stirred at 89° C. overnight. The temperature was thenincreased to 130° C. and held there for 20 minutes. Water (100 ml) wascautiously added and the reaction mixture was cooled to roomtemperature. The resulting solid was triturated with water and collectedon a filter to afford a brown solid. The solid was recrystallized twicefrom dimethyl formamide (DMF)/H₂ O to afford the subtitle compound.Melting point 265°-268° C. decomp.

F. Trans-dl-8-t-butyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

To a cold (0° C.) stirred solution of8-t-butyl-1,2,3,4,5,6,-hexahydrobenzo[f]quinolin-3-one (4.00 g; 15.66mmol) and triethylsilane (7.29 g; 62.66 mmol) in 90 ml of CH₂ Cl₂ wasadded 45 ml of trifluoroacetic acid. The cooling bath was removed andthe mixture stirred at room temperature for 24 hours. The reactionmixture was poured cautiously into saturated NaHCO₃, shaken, and thelayers separated. The organic layer was washed once with NaHCO₃, driedover Na₂ SO₄ and concentrated under vacuum to afford 5.86 g of a brownsolid. Recrystallization from ethyl acetate afforded the subtitlecompound (2.5g; 62% yield) as a beige crystalline material. Meltingpoint greater than 280° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              79.33         9.01   5.44                                          Found:     79.36         9.16   5.49                                          ______________________________________                                    

EXAMPLE 31

Preparation oftrans-dl-8-t-butyl-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared according to the procedures described inExample 30, Steps A, B, C, D, E and F and then N-methylated according tothe procedures described in Example 1, Step E using 1,2-dimethoxyethaneas the solvent, to afford 1.14 g (73% yield) of a tan solid. Meltingpoint 183°-184° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              79.66         9.29   5.16                                          Found:     80.08         9.31   4.99                                          ______________________________________                                    

EXAMPLE 32

Preparation oftrans-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A. 6-fluoro-2-pyrrolidinyl-3,4-dihydronaphthalene.

The subtitle compound was prepared according to the procedures describedin Example 1, Steps A, B and C using p-fluorophenylacetic acid as thestarting material.

B. 6-fluoro-1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene.

To 6-fluoro-2-pyrrolidinyl-3,4-dihydronaphthalene (13 g; 60.8 mmol) in200 ml of dry tetrahydrofuran (THF) was added methyliodide (30 ml; 482mmol) and the mixture was refluxed for 2 hours. The reaction mixture wasallowed to cool with stirring while crystallization took place. Thesolids were collected by filtration to afford the subtitle compound.

C. 6-fluoro-1-methyl-2-tetralone.

To the 6-fluoro-1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene affordedabove in Step B in 1700 ml of ethyl acetate was added sodium acetate(10.2 g; 124.4 mmol), acetic acid (10.2 ml; 178.2 mmol) and 102 ml ofwater. The reaction mixture was stirred at room temperature for 4 hours.The layers were separated and the organic layer was washed with brine,5% NaHCO₃, and brine. The organic layer was dried over MgSO₄ and wasconcentrated to afford 7.9 g of the subtitle compound as a darkorange-red oil (60% yield).

D. 8-fluoro-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one.

To 6-fluoro-1-methyl-2-tetralone (7.06 g; 39.6 mmol) in a round bottomedflask was added p-toluenesulfonic acid (1.23 g; 6.5 mmol) and themixture was stirred at room temperature under nitrogen for 15 minutes.Acrylamide (5.62 g; 79.2 mmol) was added and the reaction mixture washeated to 88°-90° C. under nitrogen for three days. The mixture wasdiluted with ethyl acetate and water and stirred at room temperature for1 hour. The resulting layers were separated. The organic layer waswashed three times with water, dried over MgSO₄ and concentrated to aviscous oil. The crude product was crystallized from ethyl acetate toafford 1.59 g (17% yield) of the subtitle compound. Melting point 202°C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              72.71         6.10   6.06                                          Found:     72.45         6.14   6.03                                          ______________________________________                                    

E.8-fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one.

8-fluoro-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (1.38g; 6mmol) was added to a suspension of NaH (475 mg; 20 mmol) in glyme(15 ml). The mixture was refluxed for 1.5 hours and cooled quickly toroom temperature. Methyl iodide (15 ml) was added and the mixturerefluxed for 4 hours, then allowed to cool to room temperature. Afteraddition of water, the mixture was concentrated to near dryness. Theresidue was partitioned between ethyl acetate and water. The organiclayer was washed three times with water, dried over MgSO₄ andconcentrated under vacuum. Recrystallization from hexane afforded 737 mg(56% yield) of the subtitle compound. Melting point 110°-111° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              73.45         6.57   5.71                                          Found:     73.72         6.84   5.86                                          ______________________________________                                    

F.8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Triethylsilane (1 ml; 6.12 mmol) was added to8-fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one(500 mg; 2.04 mmol) in CH₂ Cl₂ (15 ml) at room temperature. The reactionmixture was cooled to 0° C. and trifluoroacetic acid (2.6 ml) was added.After stirring at room temperature for four days, the reaction mixturewas diluted with CH₂ Cl₂ and treated with saturated NaHCO₃. Theresulting layers were separated and the organic layer was washed withsaturated NaHCO₃, dried over MgSO₄ and concentrated under vacuum to ayellow oil.

G.Trans-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The mixture obtained above in Step F was separated by columnchromatography on SiO₂ (elution with ethyl acetate/hexanes 9:1 (v:v)).The appropriate fractions containing the desired product were evaporatedto near dryness and diluted with hexanes. The resulting crystals werecollected by filtration to afford 190 mg of the subtitle compound.Melting point 130°-131° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              72.85         7.34   5.66                                          Found:     72.71         7.48   5.73                                          ______________________________________                                    

EXAMPLE 33

Preparation ofcis-dl-8-fluoro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared along with the trans-dl-isomer accordingto the procedures described in Example 32, Steps A-F.

The mixture obtained in Example 32, Step F was separated by columnchromatography on SiO₂ (elution with ethyl acetate/hexanes 9:1 (v:v)).The appropriate fractions containing the desired product were evaporatedto near dryness and diluted with hexanes. The resulting crystals werecollected by filtration to afford the title compound.

EXAMPLE 34

Preparation oftrans-dl-8-chloro-4,10b-di-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one.

The title compound was prepared along with the cis-dl-isomer (Example35) according to the procedures described in Example 32, Steps A, B, C,D, E and F using p-chlorophenylacetic acid as the starting material.Column chromatography according to Example 32, Step G afforded 523 mg ofthe title compound. Melting point 94° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.30         6.88   5.31                                          Found:     68.51         6.67   5.36                                          ______________________________________                                    

EXAMPLE 35

Preparation ofcis-dl-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared along with the trans-dl-isomer (Example34) according to the procedures described in Example 32, Steps A, B, C,D, E, and F using p-chlorophenylacetic acid as the starting material.Column chromatography according to Example 32, Step G, afforded 145 mgof the title compound.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.30         6.88   5.31                                          Found:     68.09         6.76   5.11                                          ______________________________________                                    

EXAMPLE 36

Preparation oftrans-dl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A. 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 32, Steps A, B, C andD, except using phenylacetic acid as the starting material, and usingcolumn chromatography on SiO₂, rather than recrystallization from ethylacetate, the subtitle compound was prepared as a white crystallinesolid. Melting point 123°-124° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.84         7.09   6.57                                          Found:     78.82         6.95   6.58                                          ______________________________________                                    

B. Trans-dl-10b-methyl-1,2,3,4,6,10b-octahydrobenzo[f]quinolin-3-one.

To 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (500 mg; 2.3mmol) in 50 ml of acetic acid was added 500 mg of 5% palladium oncarbon. The reaction mixture was stirred overnight at room temperatureunder an initial hydrogen pressure of 60 p.s.i. The reaction mixture wasfiltered and concentrated to dryness. The residue was partitionedbetween ethyl acetate and water. The organic layer was washed twice withsaturated NaHCO₃, and with water, and then dried over MgSO4 andconcentrated under vacuum. The residue was triturated with ether toafford 180 mg (36% yield) of the subtitle compound. Melting point178°-179° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.10         7.96   6.51                                          Found:     78.38         8.02   6.36                                          ______________________________________                                    

EXAMPLE 37

Preparation oftrans-dl-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

By following the procedures described in Example 36,trans-dl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared. To 4 ml of glyme was added NaH (31 mg; 1.26 mmol) andtrans-dl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(130 mg; 0.6 mmol). The reaction mixture was refluxed for 1.5 hours.After cooling to room temperature, 10 ml of methyl iodide was added andthe reaction mixture refluxed for 3 hours. Water was added and themixture concentrated to near dryness. The residue was partitionedbetween ethyl acetate/water. The organic layer was washed three timeswith water, dried over MgSO₄ and concentrated under vacuum. The residuewas triturated with petroleum ether to afford 60 mg (44% yield) of thetitle compound. Melting point 93° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.56         8.35   6.11                                          Found:     78.29         8.16   6.03                                          ______________________________________                                    

EXAMPLE 38

Preparation oftrans-dl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 32, Steps A, B, C, D,and F except using p-chlorophenylacetic acid as the starting material,the compound8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared as a mixture of cis and trans isomers.

The mixture was purified by HPLC (Reverse phase, CN), eluting withTHF:isooctane (48% THF by volume) to afford 32 mg of the title compound.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.33         6.46   5.61                                          Found:     67.53         6.35   5.73                                          ______________________________________                                    

EXAMPLE 39

Preparation ofcis-dl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared along with the trans-dl-isomer (Example38) according to the procedures described in Example 38. Thecis-dl-isomer was also obtained by HPLC purification using theprocedures described in Example 38, followed by trituration with diethylether.

EXAMPLE 40

Preparation of trans- and cis- R (-)8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

A. 6-chloro-1-methyl-2-tetralone.

By following the procedures described in Example 32, Steps A, B and C,except using p-chlorophenylacetic acid as the starting material, thesubtitle compound was prepared.

B. 1-methyl-2-(α-methylbenzylamino)-6-chloro-1,2-didehydrotetralin.

To 500 ml of toluene was added 6-chloro-methyl-2-tetralone (50.0 g;0.256 mol) and (R)-(+)-1-phenylethylamine (35 ml; 0.27 mol). The mixturewas heated to reflux for 4 hours with azeotropic removal of water. Thesolvent was removed under vacuum to afford 79 g of the subtitlecompound, along with its imine tautomer, as a yellow oil which was usedwithout further purification.

C. (5S)-5,6,7,8,9,10-hexahydro-8-hydroxy-2-chloro-5,8-dimethyl-5,9-methanobenzocycloocten-11-one.

To a stirred solution of1-methyl-2-(α-methylbenzylamino)-6-chloro-1,2-didehydrotetralin (79 g;0.25 mol.) in 500 mL of THF was added methyl vinyl ketone (23 mL; 0.28mol.). The solution was stirred at ambient temperature, under argonatmosphere, in the dark for 96 hours. Aqueous acetic acid (20%, 500 mL )was added and the mixture stirred for 2 hours. The reaction mixture waspartitioned between ethyl acetate and water. The organic phase waswashed with saturated Na₂ CO₃, and dried over Na₂ SO₄. The solvent wasremoved under vacuum to afford 82 g of the subtitle compound as brownoil which was used without further purification.

D. (R) (+)8-chloro-10b-methyl-1,2,3,5,6,10b-hexahydro-phenanthren-3-one.

To a stirred solution of sodium ethoxide prepared from sodium (6.5 g.)in ethanol (500 ml) was added the subtitle compound (82 g) from Step C.The solution was heated at 50° C. for 3 hours under nitrogen atmosphere.The solution was cooled to ambient temperature and partitioned betweendiethyl ether and water. The organic phase was washed with brine and wasdried over Na₂ SO₄ and concentrated under vacuum. The residue waspurified by chromatography on SiO₂ (eluting with 25% ethyl acetate inhexanes) to afford 34 g of the subtitle compound as a brown oil whichsolidified upon standing.

E. (R) 3-[1-(1-methyl-6-chloro-2-tetralone)] propanoic acid.

To a stirred mixture of RuCl₃.nH₂ O (620 mg, 2.99 mmol.) in a solventmixture (200 ml ) of 2 parts carbon tetrachloride, 3 parts acetonitrileand 2 parts water was added periodic acid (20.45 g; 89.7 mmol). Themixture was cooled to 0° C. and stirred for 15 minutes. To the mixturewas slowly added the subtitle compound from Step D (3.7 g; 14.95 mmol)in acetonitrile and the mixture stirred at 0° C. for 3 hours. 2-propanol(20 mL) was added and the mixture stirred for 1 hour. The reactionmixture was partitioned between ethyl acetate and water and the aqueousphase extracted three times with ethyl acetate. The combined organiclayers were filtered through diatomaceous earth and the filter cakewashed with ethyl acetate. The solution was concentrated under vacuum toafford 1.74 g of the subtitle compound which was used without furtherpurification.

F.(R)(+)-8-chloro-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one.

To a stirred solution of the subtitle compound from Step E (1.74 g;6.457 in 15 ml of 2-propanol was added ammonia (1 mL ) and the tubereactor sealed. The reaction mixture was heated to 180° C. for 15minutes. The mixture was cooled to room temperature and was concentratedunder vacuum to a brown glassy solid. The solid was taken up in ethylacetate, filtered through SiO₂, eluting with ethyl acetate, to affordthe subtitle compound as a pale solid. A sample was crystallized fromdiethyl ether/hexane to afford 219 mg of the subtitle compound. Meltingpoint 61°-63° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.88         5.70   5.65                                          Found:     67.54         5.65   5.44                                          ______________________________________                                    

Optical rotation:589 nm=-40.32°

(C=1, methanol) 365 nm=-185.48°

G.8-chloro-10b-methyl-1,2,3,4,4a,5,6,10-octahydrobenzo[f]quinolin-3-one.

To a stirred solution of the subtitle compound from Step F (776 mg; 3.1mmol) and triethylsilane (4.95 ml; 31 mmol) in CH₂ Cl₂ at 0° C. wasadded trifluoroacetic acid (4.82 ml; 6.26 mmol). The solution was slowlywarmed to room temperature and stirred for 48 hours. The reactionmixture was diluted with ethyl acetate, neutralized with Na₂ CO₃,extracted with ethyl acetate and concentrated under vacuum to afford 790mg of crude product that included the subtitle compound.

H.Trans-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10-octhydrobenzo[f]-quinolin-3-one.

Chromatography on SiO₂ (ethyl acetate as eluent) of the crude productfrom Step G afforded 341 mg of the subtitle compound. Melting point135°-137° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.33         6.46   5.61                                          Found:     67.41         6.55   5.36                                          ______________________________________                                    

Optical rotation:589 nm=+113.86°

(C=1, CHCl₃) 365 nm=+371.29°

EXAMPLE 41

Preparation ofcis-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10-octahydrobenzo[f]quinolin-3-one.

The title compound was prepared along with the trans-isomer (Example 40)by the procedures described in Example 40, Steps A-G. Chromatography onSiO₂ (ethyl acetate as eluent) of the crude product from Example 40,Step G afforded 91 mg of the title compound. Melting point 178°-181° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.33         6.46   5.61                                          Found:     66.73         6.73   5.36                                          ______________________________________                                    

Optical rotation:589 nm=+199.10°

(C=1, CHCl₃) 365 nm=+660.63°

EXAMPLE 42

Preparation oftrans-4-ethyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 40, Steps A, B, C, D, Eand F using phenylacetic acid as the starting material and usingethylamine rather than ammonia, and digylme rather ethylene glycol inStep F, the compound4-ethyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one wasprepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated byfollowing the procedures described Example 22 except that the reactionwas carried out at 70° C. over 7 hours to afford a crude reactionmixture. The reaction mixture was filtered and the solvents evaporatedunder vacuum to afford a glassy solid residue. The crude product waspurified by chromatography on SiO₂ (gradient elution from 100% hexanesto 100% CHCl₃) to afford 92 mg of the title compound as a colorless oil.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.97         8.70   5.76                                          Found:     79.07         8.90   5.56                                          ______________________________________                                    

EXAMPLE 43

Preparation oftrans-4-n-butyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 40, Steps A, B, C, D, Eand F using phenylacetic acid as the starting material and in Step Fusing n-butylamine rather than ammonia and dimethoxyethane rather thanethylene glycol, the compound4-n-butyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one wasprepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated byfollowing the procedures described Example 22 except that the reactionwas carried out at 60° C. over 7 hours and worked up according to theprocedures described in Example 42 to afford 61 mg of the title compoundas a colorless oil.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              77.10         9.35   5.00                                          Found:     77.44         9.28   4.95                                          ______________________________________                                    

EXAMPLE 44

Preparation oftrans-4-(4-methoxybenzyl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3one.

A. (R) 3-[1-(1-methyl-6-chloro-2-tetralone)] propanoic acid.

By following the procedures described in Example 40, Step A, B, C, D andE, using p-chlorophenyl acetic acid as the starting material, thecompound 3-[-(methyl-6-chloro-2-tetralone)] propanoic acid was prepared.

B.4-(4-methoxybenzyl)-8-chloro-10b-methyl-1,2,3,4,6,10b-hexa-hydrobenzo[f]quinolin-3-one.

To 40 ml of dimethoxyethane was added3-[1-(1-methyl-6-chloro-2-tetralone)]-propanoic acid (2g) andp-methoxybenzylamine (5 ml) in a sealed tube reactor. The solution washeated at 120° C. overnight. After allowing the reaction mixture to coolto room temperature, the solvent was removed under vacuum. The residuewas dissolved in CHCl₃, washed sequentially with 1N HCl, water,saturated NaHCO₃, and brine. The organic phase was dried over Na₂ SO₄and concentrated under vacuum. The residue was chromatographed on SiO₂(gradient elution from 100% hexanes to 100% ethyl acetate) to afford 394mg of the subtitle compound as an oil.

C.Trans-4-(4-methoxybenzyl)-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

To a stirred solution of subtitle compound from Step B (693 mg) in CH₂Cl₂ (2.5mL) under a nitrogen atmosphere was added triethylsilane (1.4ml) The reaction mixture was stirred for 15 minutes. To the solution wasadded 1.5 mL of trifluoroacetic acid and the reaction mixture stirred atroom temperature overnight. The reaction mixture was partitioned betweenCHCl₃ and saturated NaHCO₃. The organic phase was dried over Na₂ SO₄ andthe solvent removed under vacuum. The residue was purified bychromatography on SiO₂ (25% ethyl acetate in hexanes as eluent). Theproduct containing fractions were evaporated under vacuum to afford 459mg of the subtitle compound as a foam. Melting point 55°-60° C.

    ______________________________________                                        Elemental Analysis:                                                                           C       H      N                                              ______________________________________                                        Calculated (+ 1/2 mol H.sub.2 O)                                                                69.74     6.65   3.70                                       Found:            70.27     6.49   3.68                                       ______________________________________                                    

EXAMPLE 45

Preparation oftrans-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 40, Steps A, B, C, D, Eand F using phenylacetic acid as the starting material and in Step Fusing methylamine rather than ammonia and diglyme rather than ethyleneglycol, the compound4-methyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one wasprepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated byfollowing the procedures described in Example 22 except that thereaction was carried out at 60° C. over 7 hours. The reaction mixturewas filtered and solvent evaporated under vacuum. The residue waspurified by chromatography on SiO₂ (CHCl₃ as eluent) followed byrecrystallization from ethyl acetate/hexanes to afford 154 mg of thetitle compound. Melting point 111°-113° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              78.56         8.35   6.11                                          Found:     78.33         8.62   6.14                                          ______________________________________                                    

EXAMPLE 46

Preparation oftrans-dl-9-nitro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compound trans-dl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 21. Tothis compound (8.0 g; 39.75 mmol) in 320 ml of a mixture of 1:1 (V:V)glacial acetic acid and concentrated sulfuric acid at 0° C. was added1.4 equivalents of 90% fuming nitric acid at a rate which did not allowthe temperature to rise above 10° C. The mixture was stirred for 30minutes at 0° C. and then was poured onto ice. The resulting solid wascollected by filtration and recrystallized from a DMF/water mixture toyield 5.40 g (55%) of the titled compound as a yellow solid. Meltingpoint>300° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              63.40         5.73   11.38                                         Found:     63.61         5.97   11.39                                         ______________________________________                                    

EXAMPLE 47

Preparation oftrans-dl-9-nitro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one wasprepared according to the procedures described in Example 12. The titlecompound was prepared according to the procedure described in Example 46usingtrans-dl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one asthe starting material except that the reaction was quenched with waterand the product was recrystallized from ethyl acetate/hexanes. Meltingpoint 172°-172.5° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              64.60         6.20   10.76                                         Found:     64.80         6.34   10.85                                         ______________________________________                                    

EXAMPLE 48

Preparation oftrans-dl-9-amino-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-9-nitro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 47. Thiscompound (700 mg, 2.69 mmol) was dissolved in 100 ml of ethanol and 100mg of 10% palladium on carbon was added. The reaction mixture washydrogenated for 1 hour under 42 psi of hydrogen. The mixture wasfiltered and the filtrate concentrated under vacuum to give a light tansolid which was recrystallized from ethyl acetate/hexanes to give 308 mgof the titled compound as a white solid. Melting point 213°-214.5° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              73.01         7.88   12.16                                         Found:     73.22         8.02   12.20                                         ______________________________________                                    

EXAMPLE 49

Preparation oftrans-dl-9-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-9-amino-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 48. To a0° C. solution of this compound (74 mg, 0.321 mmol) in 0.3 ml ofconcentrated HCl was added sodium nitrite (23 mg, 0.324 mmol) in 0.15 mlof water. The reaction mixture was stirred at 0° C. for 30 minutes thenwas added to a 0° C. solution of copper(I) chloride (35 mg, 0.353 mmol)in 0.2 ml of concentrated HCl. The reaction mixture was allowed to warmto room temperature gradually over 2.5 hours then was heated to 60° C.for 30 minutes. After cooking, the mixture was partitioned between CHCl₃and saturated NaCl. The organic layer was dried over Na₂ SO₄ andconcentrated under vacuum to give 65 mg of a solid material. The titlecompound was obtained as a white solid (59 mg) after flashchromatography on SiO₂ (10% isopropanol/ethyl acetate). Melting point228°-230° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.33         6.46   5.61                                          Found:     67.19         6.57   5.53                                          ______________________________________                                    

EXAMPLE 50

Preparation oftrans-dl-8-chloro-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one andtrans-dl-8-chloro-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one.

A. Trans-dl-4-t-butyloxycarbonyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one wasprepared according to the procedures described in Example 17. To thiscompound (1.56 g, 6.62 mmol) in 40 ml of anhydrous 1,2-dimethoxyethane(1,2-DME) was added 380 mg of sodium hydride as a 60% dispersion inmineral oil. The mixture was refluxed for 1 hour under a nitrogenatmosphere then cooled to room temperature. A solution of di-t-butyldicarbonate (1.74 g, 7.94 mmol) in 10 ml of anhydrous 1,2-DME was addedand the mixture refluxed for 1 hour. The mixture was cooled and waterwas added cautiously followed by diethyl ether. The layers wereseparated and the aqueous layer extracted with diethyl ether. Thecombined organic layers were washed with saturated NaCl, dried over Na₂SO₄, and concentrated to give an orange semi-solid which was purified bycolumn chromatography (SiO₂, 1:1 ethyl acetate/hexanes) to afford 1.2 g(54%) of the subtitled compound as a white solid.

B.Trans-dl-4-t-butyloxycarbonyl-2-phenylseleno-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

To the protected lactam afforded in Step A (1.2 g, 3.58 mmol) in 20 mlof anhydrous THF at -78° C. was added dropwise a 0.5 M solution ofpotassium hexamethyldisilazide (14.3 ml, 7.16 mmol) in toluene. After 1hour at -78° C, a solution of phenylselenylchloride (755 mg, 3.94 mmol)in 5 ml of anhydrous THF was added. The reaction mixture was allowed towarm to room temperature and stirred for 2 hours before quenching with 5ml of saturated NH₄ Cl. The mixture was partitioned between saturatedNH₄ Cl and ethyl acetate. The organic layers were dried over Na₂ SO₄ andconcentrated under vacuum to afford 2.197 g of the subtitle compound asan orange oil.

C.Trans-dl-4-t-butyloxycarbonyl-8-chloro-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-oneandtrans-dl-4-t-butyloxycarbonyl-8-chloro-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one.

To a solution of the selenide prepared above in Step B (2.197 g, 4.48mmol) in 20 ml of THF at 0° C. buffered with excess solid NaHCO₃ wasadded 1.2 equivalents of 30% hydrogen peroxide (610 mg) in 4 ml of THF.After 30 minutes, the reaction mixture was partitioned between water andethyl acetate. The organic layer was washed with saturated NaHCO₃, driedover Na₂ SO₄, and concentrated under vacuum to afford 645 mg of amixture of olefins. Separation of the Δ¹,2 olefin from the Δ^(10b),1olefin was accomplished by column chromatography on SiO₂ with 2:1mixture of hexanes/ethyl acetate. The Δ¹,2 olefin was obtained as 293 mgof a white solid (Example 50A). The more polar Δ^(10b),1 olefin isomerwas obtained as 149 mg of a white solid (Example 50B).

D. Trans-dl-8-chloro-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one anddl-8-chloro-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one.

To a solution of the protected Δ¹,2 olefin obtained in Step C (290 mg,0.869 mmol) in 20 ml of CH₂ Cl₂ was added trifluroacetic acid (0.14 ml,1.74 mmol). The reaction mixture was stirred at room temperature for onehour and then partitioned between CH₂ Cl₂ and saturated NaHCO₃. Theorganic layer was dried over Na₂ SO₄ and concentrated under vacuum. Thecrude product obtained was recrystallized from ethyl acetate to afford142 mg (70%) of white crystallinetrans-dl-8-chloro-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one(Example 50A). Melting point 227°-228° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              66.81         5.18   5.99                                          Found:     67.09         5.18   6.22                                          ______________________________________                                    

The protected Δ¹,10b olefin (149 mg, 0.446 mmol) was treated in asimilar manner as described above for the protected Δ¹,2 olefin with theexception that the crude product was purified by column chromatographyon SiO₂ (5% isopropanol/CHCl₃) to afford 65 mg (62%) ofdl-8-chloro-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one (Example 50B)as a white solid. Melting point 241°-243° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              66.81         5.18   5.99                                          Found:     67.06         5.35   5.93                                          ______________________________________                                    

EXAMPLE 51

Preparation oftrans-dl-8-bromo-4-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one.

Trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 1. Thiscompound was converted to the title compound according to the proceduresdescribed in Example 50, Steps B and C followed by recrystallizationfrom ethyl acetate/hexanes. Melting point 136°-138° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              57.55         4.83   4.79                                          Found:     57.81         4.74   4.81                                          ______________________________________                                    

EXAMPLE 52

Preparation oftrans-dl-8-chloro-4-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one.

Trans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 6. Thiscompound was converted to the title compound according to the proceduresdescribed in Example 50, Steps B and C followed by column chromatographyon SiO₂ (ethyl acetate). Melting point 124°-125° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              67.88         5.70   5.65                                          Found:     67.77         5.77   5.38                                          ______________________________________                                    

EXAMPLE 53

Preparation ofdl-8-chloro-4-methyl-2,3,4,4a,5,6-hexahydrobenzo[f]quinolin-3-one.

Trans-dl-8-chloro-4-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 52. Tothis compound (250 mg, 1 mmol) in 30 ml of anhydrous THF was added 800mg (6.8 mmol) of pyridine hydrochloride. The reaction mixture wasstirred at room temperature for seven days and then partitioned betweenethyl acetate and 1N HCl. The organic layer was washed with 1N HClfollowed by water then dried over MgSO₄ and concentrated under vacuum to10 ml volume. The title compound was crystallized from this solution andwas collected by filtration. Melting point 99° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.16         5.31   5.67                                          Found:     67.95         5.48   5.64                                          ______________________________________                                    

EXAMPLE 54

Preparation oftrans-dl-8-chloro-2-a-methyl-4-methyl-1,2,3,4,4a,10b-hexahydrobenzo[f]quinolin-3-one.

A mixture of trans-dl-8-chloro-2-(a andb)-methyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneswas prepared according to the procedure described in Example 26. To asolution of this mixture (759 mg, 2.88 mmol) at -78° C. in 15 ml ofanhydrous THF in the presence of 2.0 equivalents ofhexamethylphosphorictriamide (HMPA) was added 11.6 ml of a 0.5 Msolution of potassium hexamethyldisilazide (5.76 mmol) in toluene. Thereaction mixture was stirred at -78° C. for ninety minutes before theaddition of a solution of phenylselenyl chloride (607 mg, 3.17 mmol) in5 ml of anhydrous THF. The solution was allowed to warm to roomtemperature over a 2 hour period, quenched with a saturated NH₄ Clsolution and the mixture extracted with ethyl acetate. The combinedorganic layers were washed with saturated NH₄ Cl, dried over Na₂ SO₄,and concentrated under vacuum to afford 1.42 of a brown oil. The crudeproduct was purified by column chromatography on SiO₂ (ethyl acetate) togive 252 mg of the 6-phenylselenide. To a solution of the selenide in 10ml of THF was added 100 mg of NaHCO₃ and approximately 1.1 equivalent of3-chloroperoxybenzoic acid (m-CPBA) (142 mg of 80-85% grade of m-CPBA,658-700 mmol). After 15 minutes, the reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was extracted withethyl acetate and the combined organic layers were washed with saturatedNaHCO₃ solution, dried over Na₂ SO₄, and concentrated under vacuum. Thecrude oil so obtained was purified by flash chromatography on SiO₂ (70%ethyl acetate/hexanes) to afford 114 mg of the titled compound as awhite solid. ¹ H-NMR analysis indicated that the Δ⁵,6 olefin had beenformed and that the 2-methyl group was in the alpha orientation. Meltingpoint 130°-132° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.83         6.16   5.35                                          Found:     68.35         6.15   4.92                                          ______________________________________                                    

EXAMPLE 55

Preparation oftrans-dl-8-t-butylaminocarbonylethanediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-t-butylaminocarbonylethenediyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 25. To asolution of this compound (122 mg, 0,358 mmol) in 150 ml of anhydrousethanol was added 15 mg of 10% palladium on carbon. The mixture washydrogenated at room temperature for six hours under an initial hydrogenpressure of 40 p.s.i. The catalyst was removed by filtration throughdiatomaceous earth (Celite®) and the filtrate concentrated to give awhite solid. Proton NMR spectroscopy indicated that the reaction was notcomplete, therefore, the material was resubmitted to the same reactionconditions for an additional 6 hours. Purification of the solid obtainedwas accomplished using column chromatography on SiO₂ (20%isopropanol/ethyl acetate) to afford the title compound as a whitesolid. Melting point 178°-179° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              73.65         8.83   8.18                                          Found:     73.21         8.69   8.32                                          ______________________________________                                    

EXAMPLE 56

Preparation oftrans-dl-8-phenyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 1. To amixture of this compound (160 mg, 0.54 mmol) andtetrakistriphenylphosphine palladium (0) (19 mg, 0.02 mmol) in 1.2 ml oftoluene under a nitrogen atmosphere was added 0.6 ml of a 2 M solutionof aqueous Na₂ CO₃ followed by phenylboronic acid (80 mg, 0.653 mmol).The reaction mixture was heated at 80° C. for 18 hours. The mixture wasallowed to cool and then partitioned between 75 ml of CH₂ Cl₂ (75 ml)and 25 ml of 2 M aqueous Na₂ CO₃ with 2 ml of concentrated NH₄ OH added.The organic layer was dried over MgSO₄ and concentrated to give a tansolid. The title compound (106 mg, 67%) as a white crystalline solid,was obtained after flash chromatoghraphy on SiO₂ (5% isopropanol/CHCl₃)and trituration of the product with hexane. Melting point 186.5°-187.5°C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              82.44         7.26   4.81                                          Found:     82.38         7.12   5.08                                          ______________________________________                                    

EXAMPLE 57

Preparation oftrans-dl-8-vinyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 1. To asealable tube was added the 8-bromo benzoquinolinone (1.00 g, 3.4 mmol),palladium (II) acetate (7.6 mg, 0.034 mmol), tri-o-tolylphosphine (41mg, 0.136 mmol), vinyltributyltin (1.24 ml, 4.25 mmol) and 5 ml ofanhydrous dioxane. Argon was bubbled through the mixture for 15 minutes.The reaction tube was sealed and heated at 100° C. with stirring for 18hours. The reaction mixture was cooled and filtered through diatomaceousearth Celite®. The filtrate was concentrated under vacuum and theresulting material was analyzed by capillary gas chromatography (G.C.)which revealed it to be a 4.7 to 1 mixture of the desired product tostarting material. Column chromatography of this mixture on SiO₂ (7%methanol/CHCl₃) afforded the title compound as 212 mg of a white solid.Melting point 89°-90° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              79.63         7.94   5.80                                          Found:     79.39         7.98   5.56                                          ______________________________________                                    

EXAMPLE 58

Preparation oftrans-dl-8-ethoxycarbonyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The compoundtrans-dl-8-iodo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 3. To asolution of the iodide (1.0034 g, 2.94 mmol) in 280 ml of ethanol wasadded tetrakistriphenylphosphine palladium (II) chloride (160 mg) and1.0 ml of triethylamine. The mixture was purged with nitrogen for 30minutes followed by purging with carbon monoxide. The reaction mixturewas fitted with a CO balloon and refluxed for 48 hours. After filtrationof the reaction mixture through diatomaceous earth, Celite®, thefiltrate concentrated under vacuum to yield an orange vicous oil. ProtonNMR spectroscopy revealed that the reaction was not complete. The oilwas resubmitted to the conditions described above for an additional 48hours. Capillary gas chromatography (G.C.). indicated the reaction was85% complete. The resulting material was purified by columnchromatography on SiO₂ (10% methanol/CHCl₃) followed by HPLC on areversed phase CN column to afforded 122 mg of the title compound.Melting point 140°-140.5° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              71.06         7.37   4.87                                          Found:     70.97         7.17   4.60                                          ______________________________________                                    

EXAMPLE 59

Preparation of (R)(+)-trans-4-methyl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 40, Steps A, B, C, D, Eand F using p-chlorophenylacetic acid as the starting material and inStep F using methylamine rather than ammonia and 2-propanol rather thanethylene glycol, the compound(R)(+)-4-methyl-8-chloro-10b-methyl-1,2,3,4,6,10b-hexahydro-benzo[f]quinolin-3-onewas prepared. This hexahydrobenzo[f]quinolin-3-one was reduced accordingto the procedure described in Example 40, Step G. The crude product waspurified by chromatography on SiO₂ (ethyl acetate as eluent) to afford5.6 g of the title compound as a pale oil which solidified on standing.Melting point 60°-61° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.30         6.88   5.31                                          Found:     68.14         6.94   5.27                                          ______________________________________                                    

Optical rotation:589 nm=+76.16°

(C=1, CHCl₃)

EXAMPLE 60

Preparation of (R)(+)-trans-4-methyl-8-chloro-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 59, the compound (R)(+)-trans-4-methyl-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared as a mixture (4:1 trans:cis) with its cis isomer. Astirred, cooled (-78° C.) solution of 1.4 g (5.56 mmol) of this mixturein THF (25 mL) was Created with potassium hexamethyldisilazide (12.2 mL;6.12 mmol) solution in toluene. The solution was stirred for 30 min. andtreated with a solution of phenyl selenyl chloride (1.17 g; 6.117 mmol)in 5 mL of THF. The solution was warmed to ambient temperature over 1hour and then quenched with 20 mL of saturated NH₄ Cl solution. Themixture was partitioned between ethyl acetate and water and the aqueousphase was dried over Na₂ SO₄ and was concentrated to afford adiastereomeric mixture of phenyl selenides. The crude phenyl selenideswere dissolved in 10 mL of ethyl acetate and cooled to 0° C. SaturatedNaHCO₃ solution (2 mL) was added to the solution, followed by 0.4 mL of30% H₂ O₂. The mixture was warmed to ambient temperature and was stirredfor 2 hours. The mixture was extracted with ethyl acetate and theresidue chromatographed on SiO₂ (ethyl acetate as eluent) to afford 611mg of the title compound as a waxy solid. Melting point 45°-48° C.

    ______________________________________                                        Elemental Analysis:                                                                    C           H      N                                                 ______________________________________                                        Calculated:                                                                              68.83         6.16   5.35                                          Found:     69.26         6.48   5.08                                          ______________________________________                                    

Optical rotation:589 nm=+87.38°

(C=1, CHCl₃)

EXAMPLE 61

Preparation of(R)(+)-trans-8-chloro-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one.

By following the procedures described in Example 40, Steps A, B, C, D,E, F, and G , the compound(R)(+)-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10-octahydrobenzo[f]quinolin-3-onewas prepared as a mixture (4:1) of trans and cis isomers. The mixture(1.02 g; 4.07 mmol) was dissolved in 15 mL of dioxane and treated withdichlorodicyanoquinone (1.02 g; 4.45 mmol) followed bybis(trimethylsilyl)trifluoroacetamide (4.8 mL; 17.9 mmol). The solutionwas stirred at ambient temperature for 4 hours and then was heated to100° C. for 14 hours. The reaction mixture was cooled to ambienttemperature and was partitioned between ethyl acetate and water. Theorganic phase was concentrated under vacuum and the residuechromatographed on SiO₂ (ethyl acetate as eluent) to afford 670 mg ofthe title compound as an oil. A sample was crystallized from diethylether to afford 60 mg of the title compound as a pale solid. Meltingpoint 151°-154° C.

    ______________________________________                                        Elemental Analysis:                                                                          C        H      N                                              ______________________________________                                        Calculated (+1/2 mol H.sub.2 O)                                                                65.50      5.89   5.46                                       Found:           65.67      6.06   5.40                                       ______________________________________                                    

Optical rotation:589 nm=+51.33°

(C=1, CHCl₃) 365 nm=-85.55°

EXAMPLE 62

Preparation oftrans-dl-8-trifluoromethyl-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

Trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas prepared according to the procedures described in Example 1. Amixture of the bromide (1.2 g, 4.1 mmol), sodium trifluoroacetate (2.22g, 16.3 mmol) and cuprous iodide (1.55 g, 8.1 mmol) in 25 ml ofN-methyl-2-pyrrolidinone were heated at 180° C. for 18 hours under anargon atmosphere. After cooling, the mixture was filtered through silicagel and the silica gel plug was washed with ethyl acetate. The combinedorganic layers were washed twice with water and once with brine, driedover MgSO₄, and evaporated under vacuum to afford 1.14 g of a black oilwhich crystallized on standing. The crude product was purified by flashchromatography on silica gel (ethyl acetate) followed by reverse phasechromatography (1:1 water/acetonitrile) to give 312 mg of a white solid(27% yield).

High Resolution mass spectrum. Calculated for C₁₅ H₁₃ F₃ NO(283.118480); found 283.119620.

EXAMPLE 63

Preparation of(+)-(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A.(S)-(-)-8-chloro-4-(α-methylbenzyl)-1,2,3,4,5,6-hexahydrobenzo[f]quinolin-3-one##STR12##

To a stirred solution of 6-chloro-2-tetralone (1.0 equiv., 100.0 mmol.,18.06 g) in toluene (300 ml) was added (S)-(-)-α-methylbenzylamine (1.0equiv., 100.0 mmol., 12.9 ml). The mixture was heated at reflux for 3hrs with the azeotropic removal of water (Dean-Stark). The cooledreaction mixture was concentrated in vacuo to give the enamine,(S)-6-chloro-2-(α-methylbenzyl)-3,4-dihydronaphthalene, as a purple oil.The oil was taken up in chloroform (150 ml) and saturated aqueous sodiumbicarbonate was added (150 ml). The vigorously stirred mixture wastreated with acryloyl chloride (1.05 equiv., 105.0 mmol., 8.5 ml)dropwise over 5 min. The reaction mixture was allowed to stir at ambienttemperature for 20 min., then diluted with chloroform and the layersseparated. The aqueous layer was extracted with chloroform (1x). Thecombined organics were washed with brine (1x), dried (Na₂ SO₄), andconcentrated in vacuo to give 37.9 g of a black oil. The crude oil wassubjected to HPLC on silica gel (gradient elution with hexanesincreasing to 25% ethyl acetate/hexanes) to give 19.03 g of a purple oilwhich was further purified by flash chromatography on silica gel(elution with 20% ethyl acetate/hexanes) to give 17.96 g, 53% yield ofthe title compound as a brown glass which was homogeneous by HPLCanalysis (reverse phase, C18, mobile phase:60% acetonitrile/0.5% aqueousammonium acetate buffer),thin layer chromatography (Silica gel, R_(f)=˜0.5, developed with 40% ethyl acetate/hexanes), and 300 MHz ¹ H NMRanalysis. FDMS:m/e=337. α[D]₅₈₉ =-24.75 (c=1.0, CHCl₃).

B.(-)-(4aR)-(10bR)-8-chloro-4-(S-α-methylbenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one##STR13##

A stirred solution (12.0 g; 35.4 mmol) of the product of Step A in 96%formic acid (175 ml) was treated with solid sodium cyanoborohydride (2.0equiv., 70.98 mmol., 4.46 g) every hr for 5 hrs (total of 10 equiv.,354.9 mmol., 22.3 g). The mixture was allowed to stir overnight (ca. 14hrs) at ambient temperature. The reaction mixture was concentrated invacuo to give a pale yellow paste which was taken up in dichloromethaneand washed with 1 N sodium hydroxide (1x). The aqueous layer was backextracted with dichloromethane (2x). The combined organics were washedwith brine (1x), dried (Na₂ SO₄), and concentrated in vacuo to give 12.0g of a colorless foam. Preparative HPLC of the residue on silica gel(gradient elution dichloromethane-1% ethyl acetate/dichloromethane) andcombination of the fractions that were greater than 90%diastereomerically pure gave 1.63 g of the title compound as acrystalline solid (HPLC analysis:reverse phase, C₁₈, 230 nm, mobilephase:60% acetonitrile/40% 0.5% ammonium acetate buffer).Recrystallization of the solid from ethyl acetate gave the titlecompound in diastereomerically pure form as colorless needles (greaterthan 99:1 diastereomeric purity, HPLC analysis). The fractions that wereenriched with the title compound were combined and concentrated in vacuoto give 3.0 g of a colorless foam. Fractional crystallization of thismaterial from ethyl acetate (3 crystallizations) gave an additional 870mg of pure title compound, 2.50g, 21% yield. mp 176°-177°. FDMS:m/e=339.α[D]₅₈₉ =-126.63 (c=1.0, CHCl₃). The absolute configuration of the titlecompound was elucidated by a single crystal x-ray diffraction study.

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             74.21   74.07                                                   H             6.52    6.59                                                    N             4.12    4.04                                                    ______________________________________                                    

C.(+)-(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one##STR14##

A mixture of the product of Step B (1.0 equiv., 4.09 mmol., 1.39 g) andtrifluoroacetic acid (35 ml) were combined in a round bottom flask. Thestirred mixture was heated at reflux for 2 hrs. The cooled reactionmixture was concentrated in vacuo, taken up in dichloromethane andwashed with a saturated aqueous solution of sodium bicarbonate (1x). Thelayers were separated and the aqueous layer was back extracted withdichloromethane (1x). The combined organics were washed with brine (1x),dried (Na₂ SO₄), and concentrated in vacuo to give a white solid.Recrystallization from ethyl acetate gave 0.81 g, 84% yield of the titlecompound as colorless needles. mp 241.5°-242°. FDMS:m/e=235. α[D]₅₈₉=32.61 (c=1.0, THF).

    ______________________________________                                                    Theory                                                                              Found                                                       ______________________________________                                        C             66.24   66.35                                                   H             5.99    6.10                                                    N             5.94    5.83                                                    ______________________________________                                    

EXAMPLE 64

(-)-(4aR)-(10bR)-8-chloro-1-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one ##STR15##

To a stirred solution of the product of Step C, Example 63 (1.0 equiv.,0.288 mmol., 98 mg) in dry 1,2-dimethoxyethane (5 ml) was added a 60%(w/w) oil dispersion of sodium hydride (26 mg). The mixture was heatedat reflux under a nitrogen atmosphere with stirring for 1 hr, cooled andtreated with methyl iodide (5.0 equiv., 1.44 mmol., 0.09 ml). Themixture was refluxed an additional 1.5 hrs. The cooled reaction mixturewas quenched with water (1 ml) and extracted with dichloromethane (3x).The combined organics were washed with brine (1x), dried (Na₂ SO₄), andconcentrated in vacuo to give an orange oil. Preparative thin layerchromatography on silica gel (2 mm plate, developed with ethyl acetate)gave 50 mg, 69% yield as a colorless solid. mp 71.5°-73°. α[D]₅₈₉=-74.80 (c=1.0, CHCl₃). HRMS (FAB+) Calculated for C₁₄ H₁₇NOCl:250.1003. Observed 250.0999.

EXAMPLE 65

Preparation of(+)-(4aS)-(10bS)-8-chloro-4-(methyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A.(+)-(4aS)-(10bS)-8-chloro-4-(S-α-methylbenzyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one##STR16##

A stirred solution of the product of Step A, Example 63 in 96% formicacid (20 ml) was treated with sodium cyanoborohydride in portions over 8hrs (30 equiv., 88.8 mmol., 5.58 g) at ambient temperature. The mixturewas then heated at 50° for 2 hrs. The cooled reaction mixture wasconcentrated in vacuo to give a colorless foam. The residue was taken upin dichloromethane and washed with water (1x). The aqueous layer wasback extracted with dichloromethane (2x). The combined organics werewashed with 1 N sodium hydroxide (1x), brine (1x), dried (Na₂ SO₄), andconcentrated in vacuo to give a colorless foam. Medium pressure liquidchromatography on silica gel (elution with 10% ethylacetate/dichloromethane) gave 201 mg of the product of Step B, Example63. Further elution gave 129 mg of the title compound as a colorlesssolid, 13% yield. HPLC analysis of this material (reverse phase, C18,230 nm, 60% acetonitrile/40% 0.5% aqueous ammonium acetate buffer)revealed that the material was greater than 99% diastereomerically pure.

B. (+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one ##STR17##

A stirred solution of the product of Step A (1.0 equiv., 0.359 mmol.,122 mg) in trifluoroacetic acid (6 ml) was heated at reflux for 1.5 hrs.The cooled reaction mixture was concentrated in vacuo to give a yellowsolid which was taken up in dichloromethane and washed with a saturatedsolution of sodium carbonate (1x). The aqueous layer was back extractedwith dichloromethane (1x). The combined organics were washed with brine(1x), dried (NaSO₄), and concentrated in vacuo to give(-)-(4aS)-(10bS)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-oneas a pale yellow solid. The residue was dissolved in dry1,2-dimethoxyethane (5 ml) and treated with sodium hydride (19 mg, 60%dispersion in mineral oil washed 3x with pentane). The mixture washeated at reflux for 1.5 hrs, cooled and treated with methyl iodide (5.0equiv., 1.80 mmol., 0.2 ml). The reaction mixture was heated anadditional 1.5 hrs. The cooled reaction mixture was quenched with water,and extracted with dichloromethane (3x). The combined organics werewashed with brine (1x), dried (Na₂ SO₄), and concentrated in vacuo togive an orange oil. Preparative thin layer chromatography on silica gel(2 mm plate, developed with ethyl acetate) gave the title compound (56mg, 62% yield) as a colorless solid. mp 71.5°-73°. α[D]₅₈₉ =+79.00(c=1.0, CHCl₃). HRMS (FAB+):Calculated for C₁₄ H₁₇ NOCl:250.0999.Observed 250.1002.

The following abbreviations are used in Examples 66 through 69

"HPLC SYSTEM A":40% acetonitrile in water and 0.5% ammonium acetate on aWaters Nova-Pak C-8®, at 220 nm, at 2.00 mL/min, 25° C.

"HPLC SYSTEM B":50% acetonitrile in water and 0.5% ammonium acetate onDuPont Zorbax ®C-18, at 220 nm, at 2.00 mL/min, 25° C.

"HPLC SYSTEM C":10% isopropyl alcohol in hexane on a Chiralcel OD® at254 nm at 1.00 mL/min and 25° C.

"HPLC SYSTEM D":10% isopropyl alcohol in hexane on a Chiralcel OD® at220 nm at 2.00 mL/min and 40° C.

EXAMPLE 66

Preparation of(+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one##STR18##

A. di-p-toluoyltartaric acid salt of1-(2-methoxycarbonylethyl)-2-(methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalene

A solution of trans(d,1)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(1.5 g) prepared substantially according to Example 6 in methanol (30mL) with concentrated sulfuric acid (3.5 g) was refluxed for 144 hours.The solution was concentrated to approximately 20 ml and diluted withether (50 mL), water (100 mL), and saturated sodium bicarbonate (20 mL,pH=9). The phases were separated and the aqueous phase further extractedwith ethyl acetate (100 mL) and methylene chloride (100 mL). Thecombined organic phases were dried with 4-A molecular sieves and addedto a solution of (-)-p-toluoyl-L-tartaric acid (DTTA) monohydrate (2.00g) in methanol (10 mL). All volatiles were removed under vacuum and theresulting foam digested in approximately 40 mL of methanol. The solidswere filtered and dried affording 1.01 g (50% of theory) of the saltadmixed with 6.3% of non-hydrolyzedtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.m.p. 126°-130° C.

TLC (Silica gel with toluene-ethyl acetate-acetic acid-methanol7:4:1:4):Rf=0.34 (phosphomolybdic acid visualization).

HPLC (SYSTEM A):t_(r) (min):0.48(43%, DTTA), tr=1.33(53%. free aminoester), t_(r) =3.36 (3.15%, racemate).

HPLC (SYSTEM B):tr(min) 1.06 (48.1%, DTTA), 2.77 (1.2%, unknown), 3.73(46.1%, free amino ester), 5.54 (4.5%, (title compound).

¹ H NMR (CDCl₃):δ5.43 (s, 2H), 3.57 (s, 3H), 2.38 (s, 6H).

UV (methanol):λ(ε):276(30,100).

IR (CHCl₃):1723 cm⁻¹.

B.(+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A solution of the above DTTA salt (100 mg) was stirred with toluene (5mL), water (10 mL) and sodium bicarbonate (50 mL) for 20 minutes at 25°C. The toluene layer was separated, dried (sodium sulfate), heated(90°-100° C.,18 hours), and evaporated affording the title compound.

¹ H NMR (Benzene-d₆):6.99 (dxd, 1H) , 6.83 (d, 1H) , 6.57 (d, 1H), 2.67(3H, s), 2.40 (dxt, 2H).

¹ H NMR (Benzene-d₆ with 2 equivR-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE):d 2.14 (3H, s),Displayed upfield methyl singlet at 2.10 for 5-6%(-)enantiomer.

HPLC (SYSTEM A):t_(r) (min) 3.36 (title compound).

HPLC (SYSTEM B):t_(r) (min) 5.68 (title compound).

HPLC (SYSTEM D):t_(r) (min) 13.85 (92%, title compound), 15.8 (8%, (-)enantiomer).

¹ H NMR (CDCl₃):3.07 (3 H, s).

EXAMPLE 67

Preparation of(+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one##STR19##

A. di-p-toluoyltartaric acid salt of1-(2-methoxycarbonylethyl)-2-(methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalene

A solution oftrans-d,l-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(2.3 g) in 0.85 N hydrochloric acid in methanol was allowed to refluxfor 168 hours after which, concentrated sulfuric acid (3.00 mL) andadditional methanol (100 mL) were added. After 96 hours, the mixture wasconcentrated and treated with solid sodium bicarbonate (20 g). Themixture containing1-(2-methoxycarbonylethyl)-2-(methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalenewas partitioned with ethyl acetate (100 mL) and water (100 mL). Thephases were separated and the water layer extracted with 250 mL of ofmethylene chloride. The organic phases were combined and filtered over3-A molecular sieves (15 g) into a solution of 5.9 g of(-)-p-toluoyl-L-tartaric acid monohydrate in methanol. All volatileswere removed under vacuum and the white foam dried under vacuum for 30hours affording the diastereomeric salt (6.1 g, 99%, containing 5.0% ofnon-hydrolyzed,trans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one)m.p. 126°-130° C.

The above foam (DTTA salt) (5.69 g) was digested in methanol (43° C., 32mL) and the resulting solution cooled to 25° C. The mixture was filteredand vacuum dried affording 2.92 g of DTTA salt. Recrystallization ofthis salt (2.28 g) from 30 mL of methanol gave 2.12 g ofconstitutionally pure salt (47%, 94% of theory).

HPLC (SYSTEM A):0.48 (46%, DTTA), 1.28 (.54%, amino ester), no otherimpurities detected.

B.(+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

The salt from above (1.50 g) was stirred (25° C., 10 minutes) withtoluene (30 mL), saturated aqueous sodium bicarbonate (10 mL) and water(40 mL). The phases were separated and the toluene layer was dried (3-Amolecular sieves). The resulting solution was heated (16 hours, 92° C.)and evaporated affording 0.55 g of(+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one admixed with 5-7% of theenantiomer (-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

HPLC (SYSTEM A):3.36 (97.9%, title compound).

HPLC (SYSTEM B):5.76 (99.9%, title compound).

HPLC (SYSTEM C):93% title compound and 7% (-)enantiomer.

UV (methanol) 204 (24100).

EXAMPLE 68

Preparation of(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.##STR20##

A. di-p-toluoyltartaric acid salt of 1-(2-methoxycarbonylethyl)-2-(methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalene

A solution of 90.0 gtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3one(approx. 95% purity by HPLC analysis) prepared substantially accordingto the procedures of Example 6, was stirred at reflux under nitrogen inanhydrous methanol (4 L) and sulfuric acid (98%, 200.0 mL) for 160 hours(<1.5%trans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneremaining by HPLC). The solution was concentrated under vacuum andextracted at 10°-15° C. using methylene chloride, sodium bicarbonate(700 g), and water (2 L). Treatment of the organic extracts with(+)-p-toluoyl-D-tartaric acid (DTTA) monohydrate (derived from unnaturaltartaric acid (S,S isomer), 132.9 g) in methanol (700 mL) and threecrystallizations gave 48.2 g of the purified salt (m.p. 125°-130° C.suitable for an analytical standard).

HPLC (SYSTEM A):0.48 (DTTA), 1.28 (amino ester).

UV (methanol):204 (51200), 239 (31400), 270 (2500).

B. (-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.

The DTTA salt from above (500 mg) was stirred with 10 mL of toluene, 5mL of water, and 5 mL of saturated aqueous sodium bicarbonate (25° C.).The aqueous layer was separated and extracted again with toluene (5 mL).The combined toluene extracts were washed once with saturated sodiumbicarbonate (5 mL), dried (4-A molecular sieves), and heated at 95°-105° C. (18 hours). The toluene was removed in a stream of nitrogen at 40°C. and the resulting oil triturated with hexane-ether affording thesubtitled compound.

TLC (Silica gel with toluene-ethyl acetate-acetic acid, 7:4:1):Rf=0.68.

HPLC (SYSTEM A):3.25 rain (>99%, title compound)

HPLC (SYSTEM C):31.12 min (>99% title compound), 28 min (<1%(+)enantiomer).

¹ H NMR (CDCl₃):3.22 (dxd).

IR (CHCl₃):1620 cm⁻¹

UV (methanol):205 (20800).

EXAMPLE 69

Preparation of di-p-toluoyltartaric acid salt of1-(2-methoxycarbonylethyl)-2-(methylamine)-6-chloro-1,2,3,4-tetrahydronaphthalene##STR21##

The initial resolution-isolation filtrates and the mother liquor fromthe first recrystallization from Example 68 above were combined andevaporated at 25° C. under vacuum affording a white foam (190.4 g). Thissalt (180.4 g) was extracted with cold methylene chloride, water, sodiumbicarbonate as described in Example 68. Treatment of the extracts with(-)-p-toluoyl-L-tartaric acid monohydrate (92.7 g) in methanol.(450 mL)and three cystallizations gave pure DTTA salt (57.0 g). (mp 126°-130°C.)

HPLC (SYSTEM A):0.48 mill (47%, DTTA), 1.28 (53%, amino ester).

IR (CHCl₃):1720 cm⁻¹.

UV (methanol):204 (46200), 239 (28000), 270(4200).

By substantially following the procedures described above one skilled inthe art can prepare the compounds of Formula I.

As noted above, the compounds of the present invention are useful [orinhibiting the conversion of testosterone to 5α-dihydrotestosterone(DHT), and more particularly the type 1 isozyme. Therefore, anotherembodiment of the present invention is a method for inhibiting5α-reductase by administering to a mammal in need of 5α-reductaseinhibition a 5α-reductase inhibiting dose (effective amount) of acompound according to Formula I or a pharmaceutically acceptable saltthereof. The compounds of the present invention are useful alone, or incombination with other 5α-reductase inhibitors, particularly type 2isozyme inhibitors, such as finasteride, 3-carboxy steroids described inHolt et al., J. Med. Chem. 33, 943-950 (1990) incorporated herein byreference, and the compounds disclosed in EP 0 291 245 also incorporatedherein by reference.

The term "effective amount" as used herein, means an amount of acompound of the present invention which is capable of inhibiting theconversion of testosterone to 5α-dihydrotestosterone which is catalyzedby the enzyme 5α-reductase and particularly, inhibiting 5α-reductase;and more particularly the type I isozyme. The 5α-reductase inhibitioncontemplated by the present method includes both medical therapeuticand/or prophylactic treatment, as appropriate. The specific dose ofcompound administered according to this invention to obtain therapeuticand/or prophylactic effects will, of course, be determined by theparticular circumstances surrounding the case, including, for example,the compound administered, the route of administration, and thecondition being treated. A typical daily dose will contain a nontoxicdosage level of from about 0.01 mg/kg to about 50 mg/kg of body weightof the active compound of this invention. Preferred daily dosesgenerally will be from about 0.05 to about 20 mg/kg and ideally fromabout 0.1 to about 10 mg/kg.

A variety of physiologic functions have been associated with theoverproduction 5 α-dihydrotestosterone. As such, the compounds of thisinvention are believed to have the ability to treat in mammals a varietyof disorders associated with 5α-dihydrotestosterone including benignprostatic hyperplasia (or hypertrophy), male pattern baldness, acnevulgaris, seborrhea, androgenic alopecia, hirsutism and prostaticcancer. Therefore, the present invention also provides methods oftreating the above disorders at the rates set forth above for inhibitingthe 5α-reductase catalyzed conversion of testosterone to5α-dihydrotestosterone. The compounds of the present invention are usedalone, or in combination with other 5α-reductase inhibitors,particularly type 2 isozyme inhibitors, such as finasteride, the3-carboxysteroids and compounds in EP 0 291 245, in these methods oftreatment.

The compounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular,intranasal, and topical for male pattern baldness, acne vulgaris, andhirsutism. The compounds of the present invention are preferablyformulated prior to administration. Therefore, another embodiment of thepresent invention is a pharmaceutical formulation comprising aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier,diluent or excipient therefor.

The active ingredient in such formulations comprises from 0.1% to 99.9%by weight of the formulation. By "pharmaceutically acceptable" it ismeant the carrier, diluent or excipient must be compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

The present pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients. In making thecompositions of the present invention, the active ingredient willusually be admixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be asolid, semi-solid or liquid material which acts as a vehicle, excipientor medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as asolid or in a liquid medium), so#t and hard gelatin capsules,suppositories, sterile injectable solutions, sterile packaged powders,and the like. Typical formulations designed for topical administrationare ointments, creams, gels, and lotions containing, for example, up to10% by weight of the active compound.

The following formulation examples are illustrative only and are notintended to limit the scope of the invention in any way. "Activeingredient," of course, means a compound according to Formula I or apharmaceutically acceptable salt thereof.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                            Quantity                                                                      (mg/capsule)                                              ______________________________________                                        Active ingredient     250                                                     Starch, dried         200                                                     Magnesium stearate     10                                                     Total                 460 mg                                                  ______________________________________                                    

FORMULATION 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                            Quantity                                                                      (mg/capsule)                                              ______________________________________                                        Active ingredient     250                                                     Cellulose, microcrystalline                                                                         400                                                     Silicon dioxide, fumed                                                                               10                                                     Stearic acid           5                                                      Total                 665 mg                                                  ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg

FORMULATION 3

An aerosol solution is prepared containing the following components:

    ______________________________________                                                         Weigtht                                                      ______________________________________                                        Active ingredient  0.25                                                       Ethanol            25.75                                                      Propellant 22                                                                 (Chlorodifluoromethane)                                                                          70.00                                                      Total              100.00                                                     ______________________________________                                    

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to -30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

FORMULATION 4

Tablets, each containing 60 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient        60 mg                                                Starch                   45 mg                                                Microcrystalline cellulose                                                                             35 mg                                                Polyvinylpyrrolidone                                                          (as 10% solution in water)                                                                             4 mg                                                 Sodium carboxymethyl starch                                                                            4.5 mg                                               Magnesium stearate       0.5 mg                                               Talc                     1 mg                                                 Total                    150 mg                                               ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl- pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.Sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

FORMULATION 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient         80 mg                                               Starch                    59 mg                                               Microcrystalline cellulose                                                                              59 mg                                               Magnesium stearate        2 mg                                                Total                    200 mg                                               ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

FORMULATION 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

    ______________________________________                                        Active ingredient          225 mg                                             Saturated fatty acid glycerides                                                                        2,000 mg                                             Total                    2,225 mg                                             ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        Active ingredient       50     mg                                             Sodium carboxymethyl cellulose                                                                        50     mg                                             Syrup                   1.25   ml                                             Benzoic acid solution   0.10   ml                                             Flavor                  q.v.                                                  Color                   q.v.                                                  Purified water to total 5      ml                                             ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION 8

An intravenous formulation may be prepared as follows:

    ______________________________________                                        Active ingredient        100 mg                                               Isotonic saline        1,000 ml                                               ______________________________________                                    

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

Ointments generally are prepared using either (1) an oleaginous base,i.e., one consisting of fixed oils or hydrocarbons, such as whitepetrolatum or mineral oil, or (2) an absorbant base, i.e., oneconsisting of an anhydrous substance or substances which can absorbwater, for example, anhydrous lanolin. Customarily, following formationof the base, whether oleaginous or absorbent, the active ingredient isadded in an amount affording the desired concentration.

Creams are oil/water emulsions. They consist of an oil phase (internalphase), comprising typically fixed oils, hydrocarbons, and the like,such as waxes, petrolatum, mineral oil, and the like, and an aqueousphase (continuous phase), comprising water and any water-solublesubstances, such as added salts. The two phases are stabilized by use ofan emulsifying agent, for example, a surface active agent, such assodium lauryl sulfate; hydrophilic colloids, such as acacia colloidalclays, veegum, and the like. Upon formation of the emulsion, the activeingredient customarily is added in an amount to achieve the desiredconcentration.

Gels comprise a base selected from an oleaginous base, water, or anemulsion-suspension base, such as described above. To the base is addeda gelling agent which forms a matrix in the base, increasing itsviscosity. Examples of gelling agents are hydroxypropyl cellulose,acrylic acid polymers, and the like. Customarily, the active ingredientis added to the formulation at the desired concentration at a pointpreceding addition of the gelling agent.

The amount of active ingredient incorporated into the formulation ofthis invention is not critical; the concentration should only be in arange sufficient to permit ready application of the formulation to thearea of administration in an amount which will deliver the desiredamount of active ingredient.

The following experiments were carried out to demonstrate the ability ofthe compounds of the present invention to inhibit 5α-reductase.

Cell Culture:5α-Reductase activity was measured using Hs68 human genitalskin fibroblasts which were originally purchased from the American TypeCulture Collection (Rockville, Md.). The cells were grown in Dulbecco'sModified Eagle's Medium (DMEM) plus 10% stripped fetal bovine serumwhich was supplemented with amphotericin B (0.25 mg/ml) and gentamicin(25.0 mg/ml) (GIBCO, Grand Island, N.Y.). The serum was stripped ofendogenous steroids by incubation with dextran-coated charcoal prior toits addition to the media. The cells were maintained at 37° C. in anatmosphere of 95% air, 5% CO₂ and were passaged every 7-10 days byexposure to a trypsin-EDTA solution (0.025% trypsin, 0.265 mM EDTA).Prior to the assay the Hs68 cells were harvested and plated in Falcon6-well plates (Becton Dickinson Labware, Lincoln Park, N.J.) at adensity of 6×10⁴ cells per well. The cells were allowed to grow for 4-5days or until they reached approximately 80% confluence.

Assay Method I:The substrate was prepared by dissolving unlabeledtestosterone (Sigma Chemical Co., St. Louis, Mo.) in absolute ethanolfollowed by the addition of [7-³ H (N)]-testosterone (23.3 Ci/mmole, NewEngland Nuclear, Boston, Mass.). The steroid solution was taken todryness under a stream of nitrogen and then reconstituted in media.

Assay Method II:The substrate used for this method was [¹⁴C]-testosterone (50 mCi/mmol) (New England Nuclear, Boston, Mass.). Analiquot of the substrate was taken to dryness under a stream ofnitrogen. After the addition of 30 μl of ethanol, the testosterone wasdissolved in an appropriate volume of media.

Sample Preparation:The test compounds were brought up in absoluteethanol in order to achieve the desired concentration. Subsequentdilutions of the test compounds with media were performed by the Biomek1000 Automated Laboratory Workstation (Beckman Instruments, Palo Alto,Calif.). The existing media in the sample wells was aspirated andreplaced with fresh media. Test compound was then added to the wellsfollowed by the addition of 0.5 ml of substrate. The volume of theincubation mixture was maintained at 2.0 ml. The final substrateconcentration was 12 μM. The concentration of the test compounds rangedfrom 0.001-150 μM. An additional three wells (background) containingmedia and substrate but no cells were also included to account for thenon-enzymatic metabolism of the substrate. The plates were returned tothe incubator and incubated for four hours.

At the end of the incubation the media was collected and transferred toan extraction tube containing 5 ml of toluene-ethanol (9:1), to whichhas been added 20-250 μg each. of unlabeled carrier steroids (estriol,estradiol, estrone, 5α-androstan-3α,17β-diol, 5α-androstan-3β,17β-diol,-androstene-3,17-dione, 5α-androstan-3,17-dione, testosterone, and5α-dihydrotestosterone) (Steraloids, Inc., Wilton, N.H.). In the case ofAssay Method I the extraction tube also contained 1,000 and 10,000 dpmof [4-¹⁴ C]-dihydrotestosterone (50-60 mCi/mmol) and [4-¹⁴C]-testosterone (50 mCi/mmol) (New England Nuclear, Boston, Mass.),respectively. The [¹⁴ C]-steroids were included as recovery standards toquantify procedural losses. A small amount of NaCl was also added to theextraction tubes to prevent foaming. The samples were vortexed forapproximately 30 seconds and then centrifuged for 10 minutes at 500×g.The organic phase was collected and the samples taken to dryness,redissolved in dichloromethane-methanol (9:1) and were analyzed by thinlayer chromatography using one of the methods described below.

Chromatography Method I (two-dimensional):The extracted samples wereappled to silica gel 60F₂₅₄, 0.25 mm thick, thin layer chromatographyplates (EM Science, Cincinnati, Ohio). The plates were developed in thefirst dimension with a solvent system containing dichloromethaneethylacetate-methanol-acetic acid (160:38:1.5:0.5, Mallinckrodt Inc., Paris,Ky.). The plates were removed from the tanks and allowed to dry beforethey were developed in the second dimension in a solvent systemcontaining dichloromethane-methanol-ammonium hydroxide (180:19:1,Mallinckrodt Inc., Paris, Ky.).

Chromatography Method II (one-dimensional):The extracted samples wereapplied to silica gel 60F₂₅₄, 0.25 mm thick, thin layer chromatographyplates (EM Science, Cincinnati, Ohio). The plates were developed in asolvent system containing either cyclohexane-ethyl acetate (1:1,Mallinckrodt Inc., Paris, Ky.) or chloroform-ethyl acetate (3:1,Mallinckrodt Inc., Paris, Ky.). Both of these solvent systems gaveadequate separation and enabled a greater throughput when compared tothe two-dimensional system described above.

The plates were initially viewed under 254 mm UV light and the visiblespots marked. The plates were then sprayed with primulin (AldrichChemical Co., Milwaukee, Wis.) (0.001% in acetone-water (4:1)) accordingto the method of Wright, R.S., "A reagent for the non-destructivelocalization of steroids and some other lipophilic materials on silicagel thin-layer chromatograms," J. Chromatogr., 59; 220-221 (1971) whichallowed the identification of additional steroids under 365 mm UV light.Samples derived using Assay Method II were analyzed directly using theAmbis Radioanalytic Imaging System (Ambis Systems, Inc., San Diego,Calif.). In the case of samples run using Assay Method I, the spots werescraped from the plate using a glass wool plugged Pasteur piper attachedto a vacuum line. The steroids were eluted directly into scintillationvials by the addition of 0.2 ml of dichloromethane followed by twowashes of 2.0 ml of methanol. The organic solvent was evaporated, and10.0 ml of scintillation fluid (Ready Organic, Beckman Instruments, Inc.Fullerton, Calif.) were added. Samples were analyzed by liquidscintillation spectrometry.

Following removal of the media for extraction, the cells were washedwith phosphate buffered saline (PBS, pH 7.4), and then harvested byexposure to a trypsin-EDTA solution (0.025% trypsin, 0.265 mM EDTA). Thecells were collected and centrifuged at 1400×g for 5 minutes. Thesupernatant was decanted and the cells were resuspended in PBS. Analiquot of the cell suspension was counted in a Coulter Counter Model ZM(Coulter Electronics, Ltd., Luton Beds, England). The remaining cellswere sonicated and the protein was determined according to the method ofBradford, M.M., "A rapid and sensitive method for protein quantitationof microgram quantities of protein utilizing the principle ofprotein-dye binding," Anal. Blochem., 72; 248-254 (1976). Correctionswere made for procedural losses, and the data were expressed as percentinhibition based on either steroid concentration in terms of picomolesper mg/protein or picomoles/10⁵ cells.

Evaluation results are given in Table I. Percent inhibition is used on ascale of 0-100 percent where 0 equals no activity and 100 equals totalinhibition.

                  TABLE I                                                         ______________________________________                                        Example    Concentration μM                                                                         % Inhibition                                         ______________________________________                                         1A        1.00          97.98                                                 1B        1.00          92.70                                                 2         1.00          100                                                   3         0.316         100                                                   4         0.316         82.06                                                 5         1.00          100                                                   6         1.00          100                                                   7         1.00          100                                                   8         1.00          100                                                   9         1.00          100                                                  10         1.00          100                                                  11         1.00          59.16                                                12         1.00          78.70                                                13         1.00          31.96                                                14         15.00         31.66                                                15         3.16          100                                                  16         0.316         80.00                                                17         1.00          100                                                  18         1.00          69.77                                                19         1.00          93.24                                                20         1.00          86.60                                                21         1.00          100                                                  22         0.316         40.69                                                23         0.316         76.49                                                24         0.316         4.96                                                 25         0.316         35.90                                                26A        0.316         82.56                                                26B        0.316         76.36                                                27         0.316         44.70                                                28         0.316         78.03                                                29         0.316         56.13                                                30         0.316         38.45                                                31         0.316         82.12                                                32         1.00          81.60                                                34         1.00          94.23                                                35         1.00          76.19                                                36         150.00        43.89                                                37         1.00          39.98                                                38         1.00          34.00                                                40         0.316         25.63                                                41         15.00         58.38                                                42         0.316         10.90                                                43         0.316         11.87                                                44         0.316         5.70                                                 45         3.16          72.16                                                46         15.00         69.90                                                47         0.316         49.68                                                48         0.316         4.36                                                 49         0.316         65.74                                                50A        0.316         83.28                                                50B        0.316         83.99                                                51         1.00          95.14                                                52         1.00          71.85                                                53         0.316         74.78                                                54         0.316         73.78                                                55         0.316         17.33                                                56         0.316         74.78                                                57         0.316         66.60                                                58         0.316         65.72                                                59         0.316         71.90                                                60         0.316         86.70                                                61         0.316         61.46                                                64         0.316         91.50                                                65         0.316         95.60                                                ______________________________________                                    

It should be understood that the instant specification and examples areset forth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention as defined by the appended claims.

We claim:
 1. A compound having the Formula ##STR22## where: R ishydrogen, C₁ -C₄ alkyl, unsubstituted or substituted phen(C₁ -C₄)alkyl;Zand Z¹ are independently selected from hydrogen and C₁ -C₄ alkyl or oneof Z and Z¹ combines with R⁵ to form a carbon-carbon bond; Y is hydrogenor methyl or combines with R¹ to form a carbon-carbon bond; R¹ ishydrogen or combines with one of Y or R³ to form a carbon-carbon bond;R² is hydrogen or C₁ -C₄ alkyl; R³ is hydrogen or combines with R¹ toform a carbon-carbon bond; R⁴ is hydrogen or combines with R⁵ to form acarbon-carbon-bond; R⁵ is hydrogen or combines with one of Z or Z¹ toform a carbon-carbon bond; n is 1 or 2; X is hydrogen, halogen, NO₂,cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl,amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino, amido, C₁ -C₄ alkylamido,C₁ -C₄ dialkylamido, mercapto, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl,C₁ -C₆ alkylsulfonyl, or a group --A--R⁶ where A is C₁ -C₆ alkylene C₂-C₆ alkenylene or C₂ -C₆ alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁-C₆ alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁-C₄ dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl, or apharmaceutically acceptable salt thereof; provided that (a) at least oneof R¹ and R⁵ is hydrogen; (b) when R is hydrogen, methyl, ethyl orbenzyl, X is other than hydrogen or methoxy; and (c) when R is methyl,R² is other than methyl.
 2. A compound according to claim 1 where:R ishydrogen or C₁ -C₄ alkyl; Z and Z¹ are independently hydrogen or methyl;Y is hydrogen or methyl, and is in a trans configuration in relation tothe 4a position hydrogen; R¹, R³, R⁴ and R⁵ are hydrogen; R² is hydrogenor metal; n is 1 or 2; X is halogen, CF₃, C₁ -C₆ alkyl, C₁ -C₄ alkoxy or--A--R⁶ where A is C₁ -C₄ alkylene and R⁶ is C₁ -C₄ alkoxycarbonyl; or apharmaceutically acceptable salt thereof; provided that (b) when R ishydrogen, methyl or ethyl, X is other than hydrogen or methoxy; and (c)when R is methyl, R² is other than methyl.
 3. A compound according toclaim 2 whereR is hydrogen or methyl; Z and Z₁ are hydrogen or methyl; Yis hydrogen or methyl, and is in a trans configuration in relation tothe 4a position hydrogen; R¹, R³, R⁴ and R⁵ are hydrogen; R² is hydrogenor methyl; n is 1 or 2; X is halogen, CF₃, or C₁ -C₄ alkyl; or apharmaceutically acceptable salt thereof; provided that (c) when R ismethyl, R² is other than methyl.
 4. A compound according to claim 3which istrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 5. A compound accordingto claim 3 which istrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzof]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 3 which istrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 3 which is(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 3 which is(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalformulation which comprises, in association with a pharamaceuticallyacceptable carrier, diluent, or excipient, a compound of the Formula##STR23## where: R is hydrogen, C₁ -C₄ alkyl, unsubstituted orsubstituted phen(C₁ -C₄)alkyl;Z and Z¹ are independently selected fromhydrogen and C₁ -C₄ alkyl or one of Z and Z¹ combines with R⁵ to form acarbon-carbon bond; Y is hydrogen or methyl or combines with R¹ to forma carbon-carbon bond; R¹ is hydrogen or combines with one of Y or R³ toform a carbon-carbon bond; R² is hydrogen or C₁ -C₄ alkyl; R³ ishydrogen or combines with R¹ to form a carbon-carbon bond; R⁴ ishydrogen or combines with R⁵ to form a carbon-carbone-bond; R⁵ ishydrogen or combines with one of Z or Z¹ to form a carbon-carbon bond; nis 1 or 2; X is hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto,C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group--A--R⁶ where A is C₁ -C₆ alkylene C₂ -C₆ alkenylene or C₂ -C₆alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁ -C₆ alkoxy, carboxy, C₁-C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino,amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl, or apharmaceutically acceptable salt thereof; provided that (a) at least oneof R¹ and R⁵ is hydrogen.
 10. A formulation according to claim 9 where:Ris hydrogen or C₁ -C₄ alkyl; Z and Z¹ are independently hydrogen ormethyl; Y is hydrogen or methyl, and is in a trans configuration inrelation to the 4a position hydrogen; R¹, R³, R⁴ and R⁵ are hydrogen; R²is hydrogen or methyl; n is 1 or 2; X is halogen, CF₃, C₁ -C₆ alkyl, C₁-C₄ alkoxy or --A--R⁶ where A is C₁ -C₄ alkylene and R⁶ is C₁ -C₄alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.
 11. Aformulation according to claim 10 where:R is hydrogen or methyl; Z andZ¹ are both hydrogen or methyl; Y is hydrogen or methyl, and is in atrans configuration in relation to the 4a position hydrogen; R¹, R³, R⁴and R⁵ are hydrogen; R² is hydrogen or methyl; n is 1 or 2; X ishalogen, CF₃, or C₁ -C₄ alkyl; or a pharmaceutically acceptable salt.12. A formulation according to claim 11 wherein said compound istrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one or a pharmaceutically acceptable saltthereof.
 13. A formulation according to claim 11 wherein said compoundistrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 14. A formulationaccording to claim 11 wherein said compound istrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one or a pharmaceutically acceptable saltthereof.
 15. A formulation according to claim 11 wherein said compoundis(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 16. A formulationaccording to claim 11 wherein said compound is(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 17. A method forinhibiting 5α-reductase in mammals, which comprises administering to amammal requiring 5α-reductase inhibition, a pharmaceutically effectiveamount of a compound of the Formula ##STR24## where: R is hydrogen, C₁-C₄ alkyl, unsubstituted or substituted phen(C₁ -C₄)alkyl;Z and Z¹ areindependently selected from hydrogen and C₁ -C₄ alkyl or one of Z and Z¹combines with R⁵ to form a carbon-carbon bond; Y is hydrogen or methylor combines with R¹ to form a carbon-carbon bond; R¹ is hydrogen orcombines with one of Y or R³ to form a carbon-carbon bond; R² ishydrogen or C₁ -C₄ alkyl; R³ is hydrogen or combines with R¹ to form acarbon-carbon bond; R⁴ is hydrogen or combines with R⁵ to form acarbon-carbone-bond; R⁵ is hydrogen or combines with one of Z or Z¹ toform a carbon-carbon bond; provided that at least one of R¹ and R⁵ ishydrogen; n is 1 or 2; X is hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₆alkyl, C₁ -C₆ alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄alkylamino, C₁ -C₄ dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄dialkylamido, mercapto, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, or a group --A--R⁶ where A is C₁ -C₆ alkylene C₂ -C₆alkenylene or C₂ -C₆ alkynylene; and R⁶ is halogen, hydroxy, CF₃, C₁ -C₆alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl, or apharmaceutically acceptable salt thereof.
 18. A method according toclaim 17 where R is hydrogen or C₁ -C₄ alkyl;Z and Z¹ are independentlyhydrogen or methyl; Y is hydrogen or methyl, and is in a transconfigruation in relation to the 4a position hydrogen; R¹, R³, R⁴ and R⁵are hydrogen; R² is hydrogen or methyl; n is 1 or 2; X is halogen, CF₃,C₁ -C₆ alkyl, C₁ -C₄ alkoxy or --A--R⁶ where A is C₁ -C₄ alkylene and R⁶is C₁ -C₄ alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.19. A method according to claim 18 where:R is hydrogen or methyl; Z andZ¹ are both hydrogen or methyl; Y is hydrogen or methyl; and is in atrans configuration in relation to the 4a position hydrogen; R¹, R³, R⁴and R⁵ are hydrogen; R² is hydrogen or methyl; n is 1 or 2; X ishalogen, CF₃, or C₁ -C₄ alkyl; or a pharmaceutically acceptable saltthereof.
 20. A method according to claim 19 wherein said compound istrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 21. A method according toclaim 19 wherein said compound istrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 22. A method according toclaim 19 wherein said compound istrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 23. A method according toclaim 19 wherein said compound is(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 24. A method according toclaim 19 wherein said compound is(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 25. A method of treatingbenign prostatic hyperplasia in a mammal comprising administering to amammal in need of treatment from benign prostatic hyperplasia, aneffective amount of a compound of claim
 1. 26. A method of treatingbenign prostatic hyperplasia in a mammal comprising administering to amammal in need of treatment from benign prostatic hyperplasia, aneffective amount of a compound of claim
 2. 27. A method of treatingbenign prostatic hyperplasia in a mammal comprising administering to amammal in need of treatment from benign prostatic hyperplasia, aneffective amount of a compound of claim
 3. 28. The method of claim 27employingtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 29. The method of claim27 employingtrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 30. The method of claim27 employing trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one or a pharmaceutically acceptable salt thereof.
 31. Themethod of claim 27 employing(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 32. The method of claim27 employing(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 33. A method of treatingmale pattern baldness in a mammal comprising administering to a mammalin need of treatment from male pattern baldness, an effective amount ofa compound of claim
 1. 34. A method of treating male pattern baldness ina mammal comprising administering to a mammal in need of treatment frommale pattern baldness, an effective amount of a compound of claim
 2. 35.A method of treating male pattern baldness in a mammal comprisingadministering to a mammal in need of treatment from male patternbaldness, an effective amount of a compound of claim
 3. 36. The methodof claim 35 employingtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 37. The method of claim35 employingtrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 38. The method of claim35 employing trans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one or a pharmaceutically acceptable salt thereof.
 39. Themethod of claim 35 employing(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 40. The method of claim35 employing(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 41. A method of treatingprostatic cancer in a mammal comprising administering to a mammal inneed of treatment from prostatic cancer, an effective amount of acompound of claim
 1. 42. A method of treating prostatic cancer in amammal comprising administering to a mammal in need of treatment fromprostatic cancer, an effective amount of a compound of claim
 2. 43. Amethod of treating prostatic cancer in a mammal comprising administeringto a mammal in need of treatment from prostatic cancer, an effectiveamount of a compound of claim
 3. 44. The method of claim 43 employingtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 45. The method of claim43 employingtrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 46. The method of claim43 employingtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 47. The method of claim43 employing(31)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 48. The method of claim43 employing(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 49. A method of treatingandrogenic alopecia in a mammal comprising administering to a mammal inneed of treatment for androgenic alopecia, an effective amount of acompound of claim
 1. 50. A method of treating androgenic alopecia in amammal comprising administering to a mammal in need of treatment fromandrogenic alopecia, an effective amount of a compound of claim
 2. 51. Amethod of treating androgenic alopecia in a mammal comprisingadministering to a mammal in need of treatment from androgenic alopecia,an effective amount of a compound of claim
 3. 52. The method of claim 51employingtrans-dl-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octa-hydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 53. The method of claim51 employingtrans-dl-4,8-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo-[f]cluinolin-3-oneor a pharmaceutically acceptable salt thereof.
 54. The method of claim51 employingtrans-dl-8-bromo-4-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 55. The method of claim51 employing(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.
 56. The method of claim51 employing(+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,5,6,10b-octahydrobenzo[f]quinolin-3-oneor a pharmaceutically acceptable salt thereof.